RARE DISEASE
Lymphangioleiomyomatosis
Lymphangioleiomyomatosis
Lymphangioleiomyomatosis
Synonyms: LAM
Synonyms: LAM
Synonyms: LAM
Drug discovery
5
drugs
With orphan designations
Overview
Lymphangioleiomyomatosis (LAM) is a rare, progressive multisystem neoplasm characterized by cystic lung destruction, lymphatic abnormalities, and renal angiomyolipomas. Driven by TSC1/TSC2 mutations causing mTOR pathway dysregulation, it predominantly affects women of reproductive age. Key features include dyspnea, recurrent pneumothoraces, chylous effusions, and progressive respiratory decline. Diagnosis relies on high-resolution CT, VEGF-D testing, and genetic evaluation. mTOR inhibitors (e.g., sirolimus) stabilize lung function and reduce complications [7].
Burden
50–80% experience pneumothorax (recurrent in most), 20–30% develop chylous complications [3][4][19].
Progressive lung function decline (FEV1 loss: 75–120 mL/year) [5][19].
10-year survival ~70%, with respiratory failure as the leading cause of mortality [3][4].
Significant quality-of-life impact due to dyspnea, fatigue, and frequent interventions [2][6].
Therapies
mTOR inhibitors: Sirolimus stabilizes lung function, reduces angiomyolipoma size, and resolves chylous effusions [2][6][10].
Pneumothorax management: Early pleurodesis (reduces recurrence from >70% to ~30%) [5][6].
Advanced care: Oxygen therapy, pulmonary rehabilitation, and lung transplantation (post-transplant survival ~12 years) [6][13].
Categories: rare genetic diseases, rare respiratory diseases, rare transplant-related disorders
Research Papers
680 drug discovery papers about Lymphangioleiomyomatosis, with 5 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
680 drug discovery papers about Lymphangioleiomyomatosis, with 5 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2025-07-11 | Modulation of infiltrating CD206+ macrophages restricts progression of pulmonary lymphangioleiomyomatosis.
Lymphangioleiomyomatosis (LAM) is a low-grade neoplasm caused by the proliferation of tuberous sclerosis complex (TSC) 1- or TSC2-deficient LAM cells, resulting in progressive cystic lung disease. The currently approved treatment for LAM delays disease progression but the disease recurs if treatment is discontinued. Therefore, new therapeutic targets and/or strategies are necessary for a cure. Immunosuppressive M2-like macrophages are involved in the progression of various cancers, but their role in the pathophysiology of LAM and as a putative therapeutic target is unknown. To identify the different immune cell populations involved in LAM, we generated a single-cell transcriptomic map of pulmonary LAM. Interactions between macrophages and LAM cells were studied using the Visium spatial transcriptomic platform and immunofluorescence staining on human pulmonary LAM specimens. Direct co-culture models were used to characterise the influence of TSC2-deficient cells on macrophage differentiation. The efficacy of targeting M2-like macrophages was assessed in preclinical mouse models of TSC2-deficient subcutaneous tumours treated with RP-182, a synthetic peptide which reprogrammes macrophages towards an antitumour M1-like phenotype. Single-cell RNA-sequencing analysis revealed that the majority of macrophages in pulmonary LAM display immunosuppressive markers, including CD206/MRC1 and CD163. Spatial transcriptomic and immunofluorescence analyses showed that M2 macrophages are in close proximity to LAM cells and that LAM cells that are in close proximity to macrophages highly express macrophage-homing factor chemokine ligand CXCL12. In vitro, co-culture of human and mouse macrophages with TSC2-deficient cells resulted in the upregulation of M2-marker-expressing macrophages. Targeting M2 macrophages via treatment with the CD206 modulator RP-182 impaired the growth of TSC2-deficient tumours in vivo. LAM cells recruit and polarise macrophages towards an M2 phenotype. M2-like CD206high macrophages may represent a potential therapeutic target in LAM.
2022-03-21 | Vasohibin-1 and -2 in pulmonary lymphangioleiomyomatosis (LAM) cells associated with angiogenic and prognostic factors.
Lymphangioleiomyomatosis (LAM) is a rare pulmonary neoplasm, clinically associated with dyspnea and respiratory failure. Current therapeutic modalities do not necessarily reach satisfactory outcome and novel therapeutic approaches are currently warranted. Therefore, in this study, we focused on vasohibin-1 (VASH1) and -2 (VASH2); VASH1 terminated and VASH2 promoted angiogenesis. In addition, both VASH1/2 were reported to influence the progression of various human malignancies. We first performed hierarchical clustering analysis to attempt to classify 36 LAM cases into three different clusters according to immunoreactivity of VASH1/2 and other angiogenic and prognostic factors of LAM; VEGFR1/2/3, p-mTOR, p-S6, p-4EBP, ERα, PgR, MMP2, and MMP9. The cluster harboring higher angiogenic factors had higher VASH1/2 status. VASH1 was significantly positively correlated with VEGFR2, MMP9, and p-mTOR (p-value <0.05), and VASH2 with both angiogenic and prognostic factors including VEGFR1, PgR, MMP9, p-mTOR, p-S6, and p-4EBP (p-value <0.05). Subsequent PCR array of angiogenic genes demonstrated that high VASH1 mRNA was significantly positively associated with the status of SPHK1 and TYPM, lower EGF and EFNB2 (p-value <0.05), and high VASH2 mRNA negatively with MMP2 (p-value <0.05). VASH1 was considered to be up-regulated by activation of angiogenesis, whereas VASH2 could influence the angiogenesis and progression of LAM.
2009-09-14 | Successful factor XIII administration for persistent chylothorax after lung transplantation for lymphangioleiomyomatosis.
Lung transplantation has emerged as a viable treatment option for patients with end-stage lymphangioleiomyomatosis (LAM), and therapeutic outcome results reported thus far have been satisfactory. However, persisting chylothorax after transplantation for LAM remains a challenging problem, and the optimal management has not been decided. We present the case with persistent chylothorax after lung transplantation for LAM, in which the intravenous administration of a tissue repair factor (human factor XIII) resulted in complete resolution of chylous effusion without performing additional invasive treatments, leading to a successful transplant outcome.
2008-03-28 | Effect of a gonadotrophin-releasing hormone analogue on lung function in lymphangioleiomyomatosis.
Lymphangioleiomyomatosis (LAM), a multisystem disease occurring primarily in women, is characterized by cystic lung destruction, and kidney and lymphatic tumors, caused by the proliferation of abnormal-appearing cells (ie, LAM cells) with a smooth muscle cell phenotype that express melanoma antigens and are capable of metastasizing. Estrogen receptors are present in LAM cells, and this finding, along with reports of disease progression during pregnancy or following exogenous estrogen administration, suggest the involvement of estrogens in the pathogenesis of LAM. Consequently, antiestrogen therapies have been employed in treatment. The goal of this prospective study was to evaluate the efficacy of triptorelin, a gonadotrophin-releasing hormone analogue, in 11 premenopausal women with LAM. Patients were evaluated at baseline and every 3 to 6 months thereafter, for a total of 36 months. Hormonal assays, pulmonary function tests, 6-min walk tests, high-resolution CT scans of the chest, and bone mineral density studies were performed. Gonadal suppression was achieved in all patients. Overall, a significant decline in lung function was observed; two patients underwent lung transplantation 1 year after study enrollment, and another patient was lost to follow-up. Treatment with triptorelin was associated with a decline in bone mineral density. Triptorelin appears not to prevent a decline in lung function in patients with LAM. Its use, however, may be associated with the loss of bone mineral density.
2005-12-31 | Modulation of Cell Migration and Invasiveness by Tumor Suppressor TSC2 in Lymphangioleiomyomatosis
The loss of TSC2 function is associated with the pathobiology of lymphangioleiomyomatosis (LAM), which is characterized by the abnormal proliferation, migration, and differentiation of smooth muscle-like cells within the lungs. Although the etiology of LAM remains unknown, clinical and genetic evidence provides support for the neoplastic nature of LAM. The goal of this study was to determine the role of tumor suppressor TSC2 in the neoplastic potential of LAM cells. We show that primary cultures of human LAM cells exhibit increased migratory activity and invasiveness, which is abolished by TSC2 re-expression. We found that TSC2 also inhibits cell migration through its N-terminus, independent of its GTPase-activating protein activity. LAM cells show increased stress fiber and focal adhesion formation, which is attenuated by TSC2 re-expression. The small GTPase RhoA is activated in LAM cells compared with normal human mesenchymal cells. Pharmacologic inhibition of Rho activity abrogates LAM cell migration; RhoA activity was also abolished by TSC2 re-expression or TSC1 knockdown with specific siRNA. These data demonstrate that TSC2 controls cell migration through its N-terminus by associating with TSC1 and regulating RhoA activity, suggesting that TSC2 may play a critical role in modulating cell migration and invasiveness, which contributes to the pathobiology of LAM.
small molecules
2026-09-06 | Contrast-enhanced ultrasound-guided precision fibrinolysis for refractory loculated chylothorax after lung transplantation: a case report.
Pleural complications remain a major source of morbidity after lung transplantation, with chylothorax posing particular therapeutic challenges. When complicated by fibrinous septation, effective drainage becomes difficult, often necessitating intrapleural fibrinolytic therapy (IPFT). However, in the early post-transplant period, blind fibrinolysis carries substantial risks, including hemorrhage and disruption of fragile bronchial anastomoses or lymphatic vessels. We report a 31-year-old woman with pulmonary lymphangioleiomyomatosis (PLAM) who developed refractory loculated chylothorax 39 days after bilateral lung transplantation. Initial chemical pleurodesis was ineffective and subsequently induced a honeycomb-like, non-communicating pleural effusion that was not amenable to conventional drainage. To balance the need for septation lysis against the risk of bleeding, contrast-enhanced ultrasound (CEUS) was integrated as a real-time guidance tool. CEUS facilitated the precise differentiation between avascular fibrin septa and vascularized pleural tissue, allowing targeted low-dose urokinase injection into isolated locules. The restoration of inter-locule communication was directly visualized, permitting early termination of fibrinolytic exposure. Subsequent drainage and repeat pleurodesis resulted in full lung re-expansion without recurrence. To our knowledge, this is the first case utilizing CEUS to guide precision fibrinolysis in a lung transplant recipient. This case provides a proof-of-concept that CEUS-guided precision fibrinolysis can transform a traditionally blind and high-risk intervention into a controlled, visualization-driven procedure. By enabling targeted intervention and real-time efficacy assessment, this approach offers a safer salvage strategy for high-risk patients.
2026-06-30 | Exploring glucocorticoid receptor signalling in lymphangioleiomyomatosis.
Lymphangioleiomyomatosis (LAM) is a rare, low-grade neoplasm that causes progressive cystic lung destruction and is often associated with renal angiomyolipomas (AMLs). Given evidence of pleiotropy linking LAM risk to pulmonary traits, we investigated whether glucocorticoid receptor (GR) signalling might influence LAM biology and clinical features. We combined cell-based studies, GR inhibition/activation assays, gene expression and single-cell RNA sequencing analyses, and hormone profiling in retrospective and prospective LAM cohorts. Cellular experiments employed murine Tsc2 -/- embryonic fibroblasts and human TSC2 -/- AML cells. Circulating steroid levels were measured in women with LAM and healthy controls, and associations with clinical variables were evaluated. In LAM/AML models, GR activation by glucocorticoids elicited transcriptional responses, whereas GR inhibition reduced clonogenic potential. GR stimulation was associated with CDKN1C upregulation through enhancer binding, and single-cell profiling suggested a shift towards slower proliferation and differentiation-prone states enriched for a LAM cell signature. Clinically, our analyses suggest that women with LAM may show altered circulating hormone profiles, including elevated adrenocorticotropic hormone (ACTH) and cortisol levels, together with reduced 17-hydroxyprogesterone, compared with controls. In a prospective cohort, ACTH levels were suggestively associated with advanced radiological disease stage. AML cells showed elevated expression of POMC, which encodes the precursor of ACTH, and POMC peptide was detected in LAM lung tissue. Our findings suggest that GR signalling may contribute to aspects of LAM cell behaviour and disease status. Further investigation of this pathway could clarify its role as a disease modifier and potential therapeutic target.
2026-06-11 | Interleukin-8 and extracellular vesicles spread senescence in Lymphangioleiomyomatosis microenvironment.
The Senescence-Associated Secretory Phenotype (SASP), a hallmark of cellular senescence, is characterized by the presence of pro-inflammatory molecules, small Extracellular Vesicles (sEVs), and proteins that remodel the extracellular matrix. For this reason, SASP might contribute to the detrimental effects of senescence by promoting inflammation and parenchymal destruction. By controlling the translation of SASP factors, the mechanistic Target of Rapamycin (mTOR) is a central regulator of senescence. As a paradigm of senescence-driven lung impairment, we developed an in vitro model of Lymphangioleiomyomatosis (LAM), a pulmonary low-grade, destructive, metastasizing rare neoplasm. Primary LAM/TSC cells, that do not express the mTOR regulator tuberin, are senescent depending on mTOR constitutive activation and induce senescence in non-LAM pulmonary lung fibroblasts (PLFs) through their conditioned medium (CM), also inducing the secretion of the SASP factor Interleukin-8 (IL-8). Here, we demonstrate the possibility to counteract both the autocrine senescence in LAM/TSC cells and senescence induced on PLFs by inhibiting CXCR2, an IL-8 receptor that controls the senescent response to IL-8 stimuli, through the small molecule SB225002. With the aim to deepen the composition of LAM/TSC CM to identify the factors involved in senescence process, we also demonstrate that LAM/TSC cells release sEVs that contribute to senescence spreading on PLFs. Interestingly, IL-8 is enriched in the LAM/TSC sEVs samples compared to PLFs. Taken together, our results indicate the therapeutic potential to interfere with senescence spreading in lung microenvironment and suggest the employment of molecules targeting senescence as a worthy pharmacological approach for LAM.
2026-06-05 | The Leiomyoma-LAM Convergence: Nrf2-Keap1-Cullin 3 Axis Hijacking, Selenium-Dependent GPx Exhaustion, and a Three-Tier Metabolic Governance Strategy Across Estrogen-Sensitive and mTOR-Driven Smooth Muscle Proliferation
This paper proposes that uterine leiomyomas and lymphangioleiomyomatosis (LAM) converge on a shared molecular vulnerability: persistent activation of Nrf2 as a stress-buffer rather than a stress-resolver. In leiomyomas, defective neddylation of the Cullin 3-RING E3 ligase complex locks Nrf2 in constitutive activation, buffering tumor cells against ROS from chronic hypoxia and estrogen-driven CYP1B1 activity. In LAM, constitutive mTORC1 activation drives Warburg-like metabolic overload forcing compensatory Nrf2 hyperactivation. In both, the selenoprotein infrastructure — GPx1, GPx4, and TrxR — is progressively exhausted by chronic Nrf2-driven synthesis demand that selenium-insufficient individuals cannot meet. A three-tier governance strategy is proposed: GLP-1 receptor agonism (systemic metabolic stabilization), selenium and mineral cofactor optimization (restoring GPx and TrxR capacity), and methylene blue (mitochondrial electron shuttle reducing the ROS load on the restored selenoprotein system). All claims are hypothesis-level requiring prospective clinical confirmation.
2026-06-03 | The SIK Axis as a Progression Modifier in Lymphangioleiomyomatosis: Nutritional Antioxidant Reserve as a Determinant of Healthy Tissue Survival in the TSC2-Driven Lung Microenvironment
Lymphangioleiomyomatosis is a rare, progressive, almost exclusively female lung disease driven by loss-of-function mutations in TSC2 genes, resulting in constitutive mTORC1 hyperactivation. This paper proposes that the SIK axis applies as a progression modifier in LAM — the rate at which healthy surrounding lung parenchymal cells survive the oxidative microenvironment created by LAM nodules is determined in part by their own selenium-dependent, NRF2-dependent, and CoQ10-dependent antioxidant reserve capacity. All claims are hypothesis-level requiring prospective investigation.
cell therapies
2026-06-26 | Decoding the Lymphangioleiomyomatosis (LAM) Niche Microenvironment via Integrative Analysis of Single Cell Multiomics and Spatial Transcriptomics.
Lymphangioleiomyomatosis (LAM) is a rare, destructive lung disease caused by mutations in TSC1 or TSC2, leading to mTORC1 hyperactivation. While mTOR inhibitor sirolimus, the only FDA approved drug for this disease, stabilizes lung function in most LAM patients, the drug does not eliminate LAM cells, underscoring a critical gap in our understanding of the tumor microenvironment and cellular heterogeneity that drive disease progression. This study provides the first comprehensive multiomics atlas of the human LAM niche, integrating single-cell/nucleus RNA-seq, single-nucleus ATAC-seq, and spatial transcriptomics to deconvolute its complex architecture. We elucidate LAM cellular heterogeneity by identifying three distinct subtypes: the canonical, uterine smooth muscle-like, mTORC1-hyperactive LAMCORE1; a novel, fibroblast-like LAMCORE2 subtype with potent extracellular matrix (ECM) remodeling activity; and LAMCORE3, a substate of LAMCORE1 that shares LAM and myogenic signatures but is characterized by a lower transcriptional activity and specific functional enrichment in protein translation.Our analysis reveals the transcriptomic heterogeneity of the LAM subtypes, orchestrated by distinct transcriptional drivers and networks. Furthermore, we uncover spatially resolved LAM-associated fibroblast (LAF) states, LAF-seed and LAF-niche, that orchestrate TGF-β signaling, ECM deposition and remodeling, and niche expansion. Spatial mapping uncovers a structured ecosystem where LAMCORE1 cells form a central core enmeshed with the lymphatic endothelium, which is surrounded by LAFs, LAMCORE2 cells, and reprogrammed immune and epithelial cells. Findings were validated through multimodal imaging technologies. Present work advances the field by providing the first high-resolution blueprint of the LAM niche microenvironment, revealing novel cell states and crosstalk that identify promising therapeutic targets.
2025-03-27 | Late living-donor kidney transplantation from the same donor after living-donor lobar lung transplantation.
Chronic kidney disease (CKD) is a common late complication associated with increased mortality after lung transplantation. Given the increased risk of infection in dialysis patients, late living-donor kidney transplantation (LDKT) provides excellent long-term survival in patients on dialysis after lung transplantation. However, recipients of living-donor lobar lung transplantation (LDLLT) might have scarce opportunity to receive LDKT due to the limited availability of living donors (LDs) for the second transplantation. We describe a successful case of late LDKT from the same donor after LDLLT. A 23-year-old woman with lymphangioleiomyomatosis underwent bilateral LDLLT of the right lower lobe from her brother and left lower lobe from her mother. Twelve years after LDLLT, she required hemodialysis for severe CKD. At the age of 37, she underwent LDKT from her mother, who was also an LD for the LDLLT. The postoperative courses of both the recipient and donor were uneventful, and the recipient remains in good physical condition (at the time of writing) despite developing recurrent lymphangioleiomyomatosis 23 years after the LDLLT, that is, 9 years after the LDKT. Her mother, the dual-organ LD, was able to return to her previous lifestyle. Late LDKT even from the same donor might be a viable option for patients developing severe CKD after LDLLT.
2024-08-08 | Single Lung Transplantation After Open Window Thoracotomy for Empyema: A Case Report.
A 41-year-old woman with lymphangioleiomyomatosis developed a bronchial anastomotic stenosis after left single lung transplantation (LTx). A part of the hyperinflated right native lung was excised in an attempt to remedy the left lung compression, which appeared to affect the bronchial anastomotic stenosis and ventilation/perfusion mismatch. However, a persistent air leak after the surgery caused empyema and an open window thoracotomy (OWT) was performed. She remained oxygen-dependent and was relisted for lung transplantation. A right single LTx on the side of OWT was performed, achieving long-term survival with no activity limitations for the patient. We report here the first successful LTx after OWT for empyema.
2020-10-19 | Adoptive T-Cell Transfer to Treat Lymphangioleiomyomatosis.
Patients with lymphangioleiomyomatosis (LAM) develop pulmonary cysts associated with neoplastic, smooth muscle-like cells that feature neuroendocrine cell markers. The disease preferentially affects premenopausal women. Existing therapeutics do not cure LAM. As gp100 is a diagnostic marker expressed by LAM lesions, we proposed to target this immunogenic glycoprotein using TCR transgenic T cells. To reproduce the genetic mutations underlying LAM, we cultured Tsc2-/- kidney tumor cells from aged Tsc2 heterozygous mice and generated a stable gp100-expressing cell line by lentiviral transduction. T cells were isolated from major histocompatibility complex-matched TCR transgenic pmel-1 mice to measure cytotoxicity in vitro, and 80% cytotoxicity was observed within 48 hours. Antigen-specific cytotoxicity was likewise observed using pmel-1 TCR-transduced mouse T cells, suggesting that transgenic T cells may likewise be useful to treat LAM in vivo. On intravenous injection, slow-growing gp100+ LAM-like cells formed lung nodules that were readily detectable in severe combined immunodeficient/beige mice. Adoptive transfer of gp100-reactive but not wild-type T cells into mice significantly shrunk established lung tumors, even in the absence of anti-PD-1 therapy. These results demonstrate the treatment potential of adoptively transferred T cells to eliminate pulmonary lesions in LAM.
2018-10-02 | Single lung transplantation for lymphangioleiomyomatosis: a single-center experience in Japan.
Lung transplantation is accepted as an effective modality for patients with end-stage pulmonary lymphangioleiomyomatosis (LAM). Generally, bilateral lung transplantation is preferred to single lung transplantation (SLT) for LAM because of native lung-related complications, such as pneumothorax and chylothorax. It remains controversial whether SLT is a suitable surgical option for LAM. The objective of this study was to evaluate the morbidity, mortality and outcome after SLT for LAM in a lung transplant center in Japan. We reviewed the records of 29 patients who underwent SLT for LAM in our hospital between March, 2000 and November, 2017. The data collected included the pre-transplant demographics of recipients, surgical characteristics, complications, morbidity, mortality and survival after SLT for LAM. The most common complication after SLT for LAM was contralateral pneumothorax (n = 7; 24.1%). Six of these recipients were treated successfully with chest-tube placement and none required surgery for the pneumothorax. The second-most common complication was chylous pleural effusion (n = 6; 20.7%) and these recipients were all successfully treated by pleurodesis. The 5-year survival rate after SLT for LAM was 79.5%. LAM-related complications after SLT for this disease can be managed. SLT is a treatment option and may improve access to lung transplantation for patients with end-stage LAM.
antibodies
2026-08-21 | T cell exhaustion in the peripheral blood of patients with sporadic lymphangioleiomyomatosis
Lymphangioleiomyomatosis (LAM) is a rare, progressive neoplastic lung disease. Lymphocytes play a central role in tumor immunity. However, circulating lymphocyte count and function have not been studied yet in sporadic LAM. Two-sample Mendelian randomization (TSMR) analysis was used to estimate the causal effect of circulating lymphocyte count on sporadic LAM. Circulating lymphocyte subsets were quantified, and inhibitory receptors (PD-1, LAG-3, TIM-3, and CTLA-4) on T cells were measured in a clinical cohort. CD4⁺ and CD8⁺ T cells were isolated and cultured to measure cytokine expression including IFN-γ and IL-4, followed by PD-1 blockade experiments using an anti-PD-1 antibody. TSMR analysis showed lower circulating lymphocyte count was associated with a higher risk of sporadic LAM. Circulating lymphocytes, mainly T cells instead of B and NK cells, were significantly decreased in sporadic LAM. Reduced CD8⁺ T cell count was significantly correlated with VEGF-D, CT gradings and FEV 1 % pred. The expression of PD-1, but not LAG-3, TIM-3, or CTLA-4, was significantly increased on both CD4⁺ and CD8⁺ T cells. The frequency of IFN-γ but not IL-4 producing CD4⁺ and CD8⁺ T cells was significantly decreased in sporadic LAM. PD-1 blockade restored the frequency of IFN-γ producing CD4⁺ and CD8⁺ T cells at least in part. Our data indicate that circulating lymphocytes, mainly T cells, are associated with the development of sporadic LAM. T cell exhaustion occurs in the peripheral blood of patients with this disease. Immune checkpoint blockade therapy may be a new strategy for sporadic LAM.
2025-10-31 | GPNMB immunohistochemistry is a useful ancillary tool for the diagnosis of pulmonary lymphangioleiomyomatosis.
Lymphangioleiomyomatosis (LAM) is a PEComa that primarily affects premenopausal women and is associated with the cystic destruction of the lung. Although smooth muscle and melanocytic markers can be helpful, histologic diagnosis of LAM remains challenging, especially in small biopsies. Glycoprotein non-metastatic melanoma protein B (GPNMB) expression has recently been identified as a highly specific and sensitive immunohistochemical marker for PEComas. Nevertheless, only a few LAM cases have been studied so far. The aim of this study was to assess the utility of GPNMB immunohistochemistry as an ancillary marker in a larger cohort of LAM samples. Immunohistochemistry for GPNMB was performed on cases of LAM (N = 15), potential differential diagnostic mimics (N = 30) and normal lung tissue (N = 2). Immunohistochemistry was assessed using the H-score method; an H-score above 100 was considered 'high'. All LAM cases showed strong cytoplasmic expression, with cell membrane accentuation in some areas. In contrast, differential diagnostic mimics were either negative or only weakly positive. Normal lung parenchyma was negative for GPNMB; however, weak-to-moderate expression was seen in alveolar macrophages in both the normal and diseased lung tissues in most cases. Considering only 'high' positivity, GPNMB immunohistochemistry showed 100% sensitivity and specificity for the diagnosis of LAM in our cohort. Based on its 100% sensitivity and specificity, GPNMB appears to be a highly valuable immunohistochemical marker for the diagnosis of pulmonary LAM. Besides its diagnostic value, the membrane positivity of GPNMB on LAM cells may predict a response to glembatumumab vedotin, an antibody-drug conjugate targeting GPNMB.
2024-10-01 | 9308 GPNMB Promotes Tumor Growth and is a Biomarker for Lymphangioleiomyomatosis (LAM)
Abstract Disclosure: E. Gibbons: None. M. Taya: None. H. Wu: None. S. Lopa: None. J. Moss: None. E.P. Henske: None. F.X. McCormack: None. S.R. Hammes: None. Lymphangioleiomyomatosis (LAM) is a rare, progressive cystic lung disease affecting almost exclusively female-sexed individuals. The cysts represent regions of lung destruction caused by smooth muscle tumors containing mutations in one of the two tuberous sclerosis (TSC) genes. mTORC1 inhibition slows but does not stop LAM advancement. Furthermore, monitoring disease progression is hindered by insufficient biomarkers. Therefore, new treatment options and biomarkers are needed. LAM cells express melanocytic markers, including Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB). The function of GPNMB in LAM is currently unknown; however, GPNMB’s unique cell surface expression on tumor versus benign cells makes GPNMB a potential therapeutic target, and persistent release of its extracellular ectodomain suggests potential as a serum biomarker. Here we establish that GPNMB regulates TSC2-null tumor cell invasion as well as TSC2-null xenograft tumor growth, and that GPNMB expression is dependent on mTORC1 signaling. Further, we show that GPNMB’s ectodomain is released from the cell surface of TSC2-null cells by ADAM10 and 17 proteases, and we identify the protease target sequence on GPNMB. In fact, mutating this cleavage sequence so that the GPNMB ectodomain can no longer be shed results in cessation of TSC2-null tumor growth. Finally, we demonstrate that GPNMB’s ectodomain is present at higher levels in LAM patient serum compared to healthy controls, and that ectodomain levels decrease with mTORC1 inhibition, making it a potential LAM biomarker. Presentation: 6/3/2024
2024-05-05 | mTOR dysregulation induces IL6 and paracrine AT2 cell senescence impeding lung repair in lymphangioleiomyomatosis
Abstract Lymphangioleiomyomatosis (LAM) is a rare disease which causes lung cysts and respiratory failure. TSC2 deficient ‘LAM cells’ with dysregulated mTOR signalling form nodules with fibroblasts causing lung injury. We examined if mTOR dysregulation could induce senescence and impair responses to lung injury. Senescence markers p21 and p16 were increased in LAM lungs and co-localised with alveolar type 2 cells. The SenMayo senescence gene panel was upregulated in LAM alveolar type 2 cells with senescence supressed by mTOR inhibition in patients. LAM cell / fibroblast spheroid cultures induced senescence markers in alveolar type 2 cell organoids, altered their growth and delayed epithelial scratch wound repair. Upstream regulator analysis predicted alveolar type 2 cell IL6 receptor activation. IL6 was produced by LAM cells, induced p16 and p21 in alveolar type 2 cells, inhibited epithelial wound resolution and was overexpressed in LAM patient serum where it was related to lung function. Wound repair in the presence of TSC2 null LAM cell / fibroblast spheroids was enhanced by the IL6 receptor antagonist Tocilizumab. Our findings show TSC2 loss induces senescence and IL6 production which are associated with impaired lung repair. Targeting IL6 signalling in parallel with mTOR inhibition, may reduce lung damage in LAM.
2023-10-01 | THU551 Glycoprotein-NMB (GPNMB) Is A Potential Lymphangioleiomyomatosis (LAM) Therapeutic Target And Biomarker
Abstract Disclosure: E. Gibbons: None. S.R. Hammes: None. Lymphangioleiomyomatosis (LAM) is a rare, progressive, destructive cystic lung disease affecting almost exclusively female-sexed individuals. Mutations in the tuberous sclerosis (TSC1 or TSC2) genes constitutively activate the mTORC1 pathway, promoting hyperproliferation of smooth muscle cells, creating small tumors throughout the lungs. These tumors, through largely unknown mechanisms, result in the formation of large cysts that replace normal alveolar space. Inhibition of mTORC1 with Sirolimus slows but does not stop LAM progression; therefore, there is a need for new LAM treatment options and biomarkers. Due to LAM’s estrogen sensitivity, female specificity, and metastatic nature, we previously proposed LAM cells originate from the uterine myometrium. We therefore designed a uterine-specific TSC2-null mouse model where all the mice generate uterine tumors characteristic of LAM and half develop lung metastases, suggesting that indeed LAM tumors may be derived from the uterus. Using bulk RNASeq analysis of uterine tissue from our mouse model, when focusing on genes regulated by estrogen and TSC2, we discovered increased expression of melanocytic markers, including Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB), a known oncogenic protein in other cancers. GPNMB was not only highly expressed in our mouse model; it was also expressed intracellularly and on the cell surface of TSC2-null cell lines and in LAM tumor cells from patient lungs and uteri. Notably, the extracellular domain of GPNMB was released from the surface of TSC2-null cell lines, suggesting that the ectodomain may also be released from TSC2-null cells in LAM patients. Here we show that, GPNMB protein and mRNA expression increased when the cells were serum starved, mimicking conditions of a tumor microenvironment. This increase was dependent on mTORC1 signaling and mRNA transcription. Knocking down GPNMB expression by siRNA had minimal effects on TSC2-null cells pro-tumorigenic functions in vitro aside from decreasing invasion. However, knocking out GPNMB in TSC2-null cells using CRISPR/Cas9 significantly decreased mouse xenograft tumor growth. Additionally, treating mice with a GPNMB antibody drug conjugate abrogated xenograft growth, highlighting GPNMB’s potential as a therapeutic target. Also, GPNMB’s ectodomain was released from the cell surface of TSC2-null cells by the proteases Adam10 and 17. Of note, the ectodomain is implicated in mediating GPNMB’s effects on tumor growth, suggesting that Adam10/17 inhibition may mitigate TSC2-null tumor growth. Importantly, the GPNMB ectodomain is a potential serum biomarker of LAM, as there was a significant increase in GPNMB ectodomain levels in patient serum as compared with healthy controls. Furthermore, serum GPNMB levels decreased in most patients after Sirolimus treatment, implicating GPNMB as a potential marker for responsiveness to treatment. Presentation: Thursday, June 15, 2023
other
2025-05-01 | Neural Crest Markers Are Therapeutic Targets for Tuberous Sclerosis and Lymphangioleiomyomatosis Neoplasms
Abstract RATIONALE: The hypothesis regarding the neural crest origin of TSC (tuberous sclerosis complex) and LAM (lymphangioleiomyomatosis) tumors has generated considerable debate. This is based on the mesenchymal phenotypes of these neoplasms and their occurrence in areas of the body that are known ontogenetic destinations for maturing neural crest cells. However, this hypothesis has not been thoroughly evaluated, limiting the potential for developing therapies that target tumorigenic neural crest cells (NCCs) and their mesenchymal derivatives. METHODS: We analyzed single-cell populations from renal cortical tissues of the B6129SF2/J wildtype mice (N=3 mice; 19078 cells) and renal cystadenomas in Tsc2+/- mice (N=4 mice; 26861 cells) used as an animal model of TSC. Distinct NCC subpopulations were identified in renal tumors based on their significant expression of 40 neural crest markers. Differential gene expression and signaling pathway analyses were performed on tumorigenic NCCs, with validation in Tsc2+/- mice and LAM tumors via immunohistochemistry, western blotting, and RT-qPCR. We employed CRISPR/Cas9 to generate knockout mouse cranial NCC lines targeting the neuro-immunomodulatory marker osteopontin (Spp1) and assessed the tumorigenic potential of Spp1WT vs. Spp1KO NCCs through migration, invasion, proliferation, and viability assays. RESULTS: Tumorigenic cranial neural crest cells constituted 0.6% of the dissociated tumor cells from the Tsc2+/- mice, representing an 80-fold increase compared to wild-type mice renal tissue. The NCCs in Tsc2+/- mice renal tumors expressed gene signatures indicating transformation, and that are distinct from endogenous immune cells and renal tissue, including secreted phosphoprotein 1 (Spp1), Clusterin (Clu), SRY-box 9 (Sox9), Lipocalin-2 (Lcn2), and cytokeratin 18 (Krt18). The expression of select tumorigenic NCC markers was validated in Tsc2+/- mice renal and hepatic tumors, pulmonary LAM lesions, and renal angiomyolipoma but not in age-matched healthy tissues. Notably, the expression levels of these tumorigenic NCC markers increased with the age of Tsc2+/- tumors, from 6 to 16 months. Knockout of Spp1 significantly reduced NCC invasion (87%), migration (92%), and proliferation (63%) without affecting cell viability. CONCLUSION: Cranial neural crest cells present in wildtype mice kidneys genetically transform and proliferate in Tsc2+/- mice, leading to renal cystadenomas. This study characterizes these tumorigenic cranial NCCs in the Tsc2+/-mice and highlights the crucial role of secreted phosphoprotein Spp1 in their transformation into tumors and as a potential therapeutic for LAM and TSC tumors. Future research will explore the therapeutic potential of other tumorigenic NCC markers resolved in our study and investigate the regulatory mechanisms driving NCC transformation.
2024-07-11 | Plasmacytoid Dendritic Cells Mediate CpG-ODN-induced Increase in Survival in a Mouse Model of Lymphangioleiomyomatosis.
Lymphangioleiomyomatosis (LAM) is a devastating disease primarily found in women of reproductive age that leads to cystic destruction of the lungs. Recent work has shown that LAM causes immunosuppression and that checkpoint inhibitors can be used as LAM treatment. Toll-like receptor (TLR) agonists can also reactivate immunity, and the TLR9 agonist CpG oligodeoxynucleotide (CpG-ODN) has been effective in treating lung cancer in animal models. In this study, we investigated the use of TLR9 agonist CpG-ODN as LAM immunotherapy in combination with checkpoint inhibitor anti-PD1 and standard of care rapamycin, and determined the immune mechanisms underlying therapeutic efficacy. We used survival studies, flow cytometry, ELISA, and histology to assess immune response and survival after intranasal treatment with CpG-ODN in combination with rapamycin or anti-PD1 therapy in a mouse model of metastatic LAM. We found that local administration of CpG-ODN enhances survival in a mouse model of LAM. We found that a lower dose led to longer survival, likely because of fewer local side effects, but increased LAM nodule count and size compared with the higher dose. CpG-ODN treatment also reduced regulatory T cells and increased the number of T-helper type 17 cells as well as cytotoxic T cells. These effects appear to be mediated in part by plasmacytoid dendritic cells because depletion of plasmacytoid dendritic cells reduces survival and abrogates T-helper type 17 cell response. Finally, we found that CpG-ODN treatment is effective in early-stage and progressive disease and is additive with anti-PD1 therapy and rapamycin. In summary, we have found that TLR9 agonist CpG-ODN can be used as LAM immunotherapy and effectively synergizes with rapamycin and anti-PD1 therapy in LAM.
2023-02-07 | Inhaled CpG increases survival and synergizes with checkpoint inhibition in lymphangioleiomyomatosis
ABSTRACT Lymphangioleiomyomatosis (LAM) is a devastating disease primarily found in women of reproductive age that leads to cystic destruction of the lungs. Recent work has shown that LAM causes immunosuppression and that checkpoint inhibitors can be used as LAM treatment. Toll-like receptor (TLR) agonists can also re-activate immunity and the TLR9 agonist, CpG-ODN, has been effective in treating lung cancer in animal models. Here we investigate the use of TLR9 agonist CpG-ODN as LAM immunotherapy in combination with checkpoint inhibitor, anti-PD1, standard of care rapamycin and determine the immune mechanisms underlying therapeutic efficacy. We used survival studies, flow cytometry, ELISA, and histology to assess immune response and survival after intranasal treatment with CpG-ODN in combination with rapamycin or anti-PD1 therapy in a mouse model of metastatic LAM. We found that local administration of CpG-ODN enhances survival in a mouse model of LAM. We found that a lower dose led to longer survival likely due to fewer local side effects but increased LAM nodule count and size compared to the higher dose. CpG-ODN treatment also reduced regulatory T cells and increased the number of Th17 helper T cells as well as cytotoxic T cells. These effects appear to be mediated in part by plasmacytoid dendritic cells (pDCs), as depletion of pDCs reduces survival and abrogates Th17 T cell response. Finally, we found that CpG-ODN treatment is effective in early stage and progressive disease and is additive with anti-PD1 therapy and rapamycin. In summary, we have found that TLR9 agonist CpG-ODN can be used as LAM immunotherapy and effectively synergizes with rapamycin and anti-PD1 therapy in LAM.
2022-03-14 | Lung-selective mRNA delivery of synthetic lipid nanoparticles for the treatment of pulmonary lymphangioleiomyomatosis.
Safe and efficacious systemic delivery of messenger RNA (mRNA) to specific organs and cells in vivo remains the major challenge in the development of mRNA-based therapeutics. Targeting of systemically administered lipid nanoparticles (LNPs) coformulated with mRNA has largely been confined to the liver and spleen. Using a library screening approach, we identified that N-series LNPs (containing an amide bond in the tail) are capable of selectively delivering mRNA to the mouse lung, in contrast to our previous discovery that O-series LNPs (containing an ester bond in the tail) that tend to deliver mRNA to the liver. We analyzed the protein corona on the liver- and lung-targeted LNPs using liquid chromatography-mass spectrometry and identified a group of unique plasma proteins specifically absorbed onto the surface that may contribute to the targetability of these LNPs. Different pulmonary cell types can also be targeted by simply tuning the headgroup structure of N-series LNPs. Importantly, we demonstrate here the success of LNP-based RNA therapy in a preclinical model of lymphangioleiomyomatosis (LAM), a destructive lung disease caused by loss-of-function mutations in the Tsc2 gene. Our lung-targeting LNP exhibited highly efficient delivery of the mouse tuberous sclerosis complex 2 (Tsc2) mRNA for the restoration of TSC2 tumor suppressor in tumor and achieved remarkable therapeutic effect in reducing tumor burden. This research establishes mRNA LNPs as a promising therapeutic intervention for the treatment of LAM.
2021-12-23 | The microRNA miR-132 is a key regulator of lymphatic vascular remodelling
ABSTRACT Lymphangiogenesis (growth of new lymphatic vessels), and lymphatic remodelling more broadly, are important for disease progression in cancer, lymphedema and the pulmonary disease lymphangioleiomyomatosis. Multiple molecular pathways which signal for aspects of lymphangiogenesis are known but little is understood about their co-ordinate regulation in lymphatic endothelial cells (LECs). Small RNA molecules co-ordinately regulate complex biological processes, but knowledge about their involvement in lymphangiogenesis is limited. Here we used high-throughput small RNA sequencing of LECs to identify microRNAs (miRs) regulating lymphatic remodelling driven by the lymphangiogenic growth factors VEGF-C and VEGF-D. We identified miR-132 as up-regulated by both growth factors, and demonstrated that inhibiting miR-132 in LECs in vitro blocked cell proliferation and tube formation, key steps in lymphangiogenesis. We showed that miR-132 is expressed in human LECs in vivo in the lymphatics of human breast tumours expressing VEGF-D. Importantly, we demonstrated that inhibiting miR-132 in vivo blocked many aspects of lymphangiogenesis in mice. Finally, we identified mRNAs regulated by miR-132 in LECs, by sequencing after RNA-protein cross-linking and Argonaute immunoprecipitation, which demonstrated how miR-132 co-ordinately regulates signalling pathways in lymphangiogenesis. This study shows miR-132 is a critical regulator of lymphangiogenesis and a potential target for therapeutically manipulating lymphatic remodelling in disease.
proteins
2025-07-11 | Modulation of infiltrating CD206+ macrophages restricts progression of pulmonary lymphangioleiomyomatosis.
Lymphangioleiomyomatosis (LAM) is a low-grade neoplasm caused by the proliferation of tuberous sclerosis complex (TSC) 1- or TSC2-deficient LAM cells, resulting in progressive cystic lung disease. The currently approved treatment for LAM delays disease progression but the disease recurs if treatment is discontinued. Therefore, new therapeutic targets and/or strategies are necessary for a cure. Immunosuppressive M2-like macrophages are involved in the progression of various cancers, but their role in the pathophysiology of LAM and as a putative therapeutic target is unknown. To identify the different immune cell populations involved in LAM, we generated a single-cell transcriptomic map of pulmonary LAM. Interactions between macrophages and LAM cells were studied using the Visium spatial transcriptomic platform and immunofluorescence staining on human pulmonary LAM specimens. Direct co-culture models were used to characterise the influence of TSC2-deficient cells on macrophage differentiation. The efficacy of targeting M2-like macrophages was assessed in preclinical mouse models of TSC2-deficient subcutaneous tumours treated with RP-182, a synthetic peptide which reprogrammes macrophages towards an antitumour M1-like phenotype. Single-cell RNA-sequencing analysis revealed that the majority of macrophages in pulmonary LAM display immunosuppressive markers, including CD206/MRC1 and CD163. Spatial transcriptomic and immunofluorescence analyses showed that M2 macrophages are in close proximity to LAM cells and that LAM cells that are in close proximity to macrophages highly express macrophage-homing factor chemokine ligand CXCL12. In vitro, co-culture of human and mouse macrophages with TSC2-deficient cells resulted in the upregulation of M2-marker-expressing macrophages. Targeting M2 macrophages via treatment with the CD206 modulator RP-182 impaired the growth of TSC2-deficient tumours in vivo. LAM cells recruit and polarise macrophages towards an M2 phenotype. M2-like CD206high macrophages may represent a potential therapeutic target in LAM.
2022-03-21 | Vasohibin-1 and -2 in pulmonary lymphangioleiomyomatosis (LAM) cells associated with angiogenic and prognostic factors.
Lymphangioleiomyomatosis (LAM) is a rare pulmonary neoplasm, clinically associated with dyspnea and respiratory failure. Current therapeutic modalities do not necessarily reach satisfactory outcome and novel therapeutic approaches are currently warranted. Therefore, in this study, we focused on vasohibin-1 (VASH1) and -2 (VASH2); VASH1 terminated and VASH2 promoted angiogenesis. In addition, both VASH1/2 were reported to influence the progression of various human malignancies. We first performed hierarchical clustering analysis to attempt to classify 36 LAM cases into three different clusters according to immunoreactivity of VASH1/2 and other angiogenic and prognostic factors of LAM; VEGFR1/2/3, p-mTOR, p-S6, p-4EBP, ERα, PgR, MMP2, and MMP9. The cluster harboring higher angiogenic factors had higher VASH1/2 status. VASH1 was significantly positively correlated with VEGFR2, MMP9, and p-mTOR (p-value <0.05), and VASH2 with both angiogenic and prognostic factors including VEGFR1, PgR, MMP9, p-mTOR, p-S6, and p-4EBP (p-value <0.05). Subsequent PCR array of angiogenic genes demonstrated that high VASH1 mRNA was significantly positively associated with the status of SPHK1 and TYPM, lower EGF and EFNB2 (p-value <0.05), and high VASH2 mRNA negatively with MMP2 (p-value <0.05). VASH1 was considered to be up-regulated by activation of angiogenesis, whereas VASH2 could influence the angiogenesis and progression of LAM.
2009-09-14 | Successful factor XIII administration for persistent chylothorax after lung transplantation for lymphangioleiomyomatosis.
Lung transplantation has emerged as a viable treatment option for patients with end-stage lymphangioleiomyomatosis (LAM), and therapeutic outcome results reported thus far have been satisfactory. However, persisting chylothorax after transplantation for LAM remains a challenging problem, and the optimal management has not been decided. We present the case with persistent chylothorax after lung transplantation for LAM, in which the intravenous administration of a tissue repair factor (human factor XIII) resulted in complete resolution of chylous effusion without performing additional invasive treatments, leading to a successful transplant outcome.
2008-03-28 | Effect of a gonadotrophin-releasing hormone analogue on lung function in lymphangioleiomyomatosis.
Lymphangioleiomyomatosis (LAM), a multisystem disease occurring primarily in women, is characterized by cystic lung destruction, and kidney and lymphatic tumors, caused by the proliferation of abnormal-appearing cells (ie, LAM cells) with a smooth muscle cell phenotype that express melanoma antigens and are capable of metastasizing. Estrogen receptors are present in LAM cells, and this finding, along with reports of disease progression during pregnancy or following exogenous estrogen administration, suggest the involvement of estrogens in the pathogenesis of LAM. Consequently, antiestrogen therapies have been employed in treatment. The goal of this prospective study was to evaluate the efficacy of triptorelin, a gonadotrophin-releasing hormone analogue, in 11 premenopausal women with LAM. Patients were evaluated at baseline and every 3 to 6 months thereafter, for a total of 36 months. Hormonal assays, pulmonary function tests, 6-min walk tests, high-resolution CT scans of the chest, and bone mineral density studies were performed. Gonadal suppression was achieved in all patients. Overall, a significant decline in lung function was observed; two patients underwent lung transplantation 1 year after study enrollment, and another patient was lost to follow-up. Treatment with triptorelin was associated with a decline in bone mineral density. Triptorelin appears not to prevent a decline in lung function in patients with LAM. Its use, however, may be associated with the loss of bone mineral density.
2005-12-31 | Modulation of Cell Migration and Invasiveness by Tumor Suppressor TSC2 in Lymphangioleiomyomatosis
The loss of TSC2 function is associated with the pathobiology of lymphangioleiomyomatosis (LAM), which is characterized by the abnormal proliferation, migration, and differentiation of smooth muscle-like cells within the lungs. Although the etiology of LAM remains unknown, clinical and genetic evidence provides support for the neoplastic nature of LAM. The goal of this study was to determine the role of tumor suppressor TSC2 in the neoplastic potential of LAM cells. We show that primary cultures of human LAM cells exhibit increased migratory activity and invasiveness, which is abolished by TSC2 re-expression. We found that TSC2 also inhibits cell migration through its N-terminus, independent of its GTPase-activating protein activity. LAM cells show increased stress fiber and focal adhesion formation, which is attenuated by TSC2 re-expression. The small GTPase RhoA is activated in LAM cells compared with normal human mesenchymal cells. Pharmacologic inhibition of Rho activity abrogates LAM cell migration; RhoA activity was also abolished by TSC2 re-expression or TSC1 knockdown with specific siRNA. These data demonstrate that TSC2 controls cell migration through its N-terminus by associating with TSC1 and regulating RhoA activity, suggesting that TSC2 may play a critical role in modulating cell migration and invasiveness, which contributes to the pathobiology of LAM.
small molecules
2026-09-06 | Contrast-enhanced ultrasound-guided precision fibrinolysis for refractory loculated chylothorax after lung transplantation: a case report.
Pleural complications remain a major source of morbidity after lung transplantation, with chylothorax posing particular therapeutic challenges. When complicated by fibrinous septation, effective drainage becomes difficult, often necessitating intrapleural fibrinolytic therapy (IPFT). However, in the early post-transplant period, blind fibrinolysis carries substantial risks, including hemorrhage and disruption of fragile bronchial anastomoses or lymphatic vessels. We report a 31-year-old woman with pulmonary lymphangioleiomyomatosis (PLAM) who developed refractory loculated chylothorax 39 days after bilateral lung transplantation. Initial chemical pleurodesis was ineffective and subsequently induced a honeycomb-like, non-communicating pleural effusion that was not amenable to conventional drainage. To balance the need for septation lysis against the risk of bleeding, contrast-enhanced ultrasound (CEUS) was integrated as a real-time guidance tool. CEUS facilitated the precise differentiation between avascular fibrin septa and vascularized pleural tissue, allowing targeted low-dose urokinase injection into isolated locules. The restoration of inter-locule communication was directly visualized, permitting early termination of fibrinolytic exposure. Subsequent drainage and repeat pleurodesis resulted in full lung re-expansion without recurrence. To our knowledge, this is the first case utilizing CEUS to guide precision fibrinolysis in a lung transplant recipient. This case provides a proof-of-concept that CEUS-guided precision fibrinolysis can transform a traditionally blind and high-risk intervention into a controlled, visualization-driven procedure. By enabling targeted intervention and real-time efficacy assessment, this approach offers a safer salvage strategy for high-risk patients.
2026-06-30 | Exploring glucocorticoid receptor signalling in lymphangioleiomyomatosis.
Lymphangioleiomyomatosis (LAM) is a rare, low-grade neoplasm that causes progressive cystic lung destruction and is often associated with renal angiomyolipomas (AMLs). Given evidence of pleiotropy linking LAM risk to pulmonary traits, we investigated whether glucocorticoid receptor (GR) signalling might influence LAM biology and clinical features. We combined cell-based studies, GR inhibition/activation assays, gene expression and single-cell RNA sequencing analyses, and hormone profiling in retrospective and prospective LAM cohorts. Cellular experiments employed murine Tsc2 -/- embryonic fibroblasts and human TSC2 -/- AML cells. Circulating steroid levels were measured in women with LAM and healthy controls, and associations with clinical variables were evaluated. In LAM/AML models, GR activation by glucocorticoids elicited transcriptional responses, whereas GR inhibition reduced clonogenic potential. GR stimulation was associated with CDKN1C upregulation through enhancer binding, and single-cell profiling suggested a shift towards slower proliferation and differentiation-prone states enriched for a LAM cell signature. Clinically, our analyses suggest that women with LAM may show altered circulating hormone profiles, including elevated adrenocorticotropic hormone (ACTH) and cortisol levels, together with reduced 17-hydroxyprogesterone, compared with controls. In a prospective cohort, ACTH levels were suggestively associated with advanced radiological disease stage. AML cells showed elevated expression of POMC, which encodes the precursor of ACTH, and POMC peptide was detected in LAM lung tissue. Our findings suggest that GR signalling may contribute to aspects of LAM cell behaviour and disease status. Further investigation of this pathway could clarify its role as a disease modifier and potential therapeutic target.
2026-06-11 | Interleukin-8 and extracellular vesicles spread senescence in Lymphangioleiomyomatosis microenvironment.
The Senescence-Associated Secretory Phenotype (SASP), a hallmark of cellular senescence, is characterized by the presence of pro-inflammatory molecules, small Extracellular Vesicles (sEVs), and proteins that remodel the extracellular matrix. For this reason, SASP might contribute to the detrimental effects of senescence by promoting inflammation and parenchymal destruction. By controlling the translation of SASP factors, the mechanistic Target of Rapamycin (mTOR) is a central regulator of senescence. As a paradigm of senescence-driven lung impairment, we developed an in vitro model of Lymphangioleiomyomatosis (LAM), a pulmonary low-grade, destructive, metastasizing rare neoplasm. Primary LAM/TSC cells, that do not express the mTOR regulator tuberin, are senescent depending on mTOR constitutive activation and induce senescence in non-LAM pulmonary lung fibroblasts (PLFs) through their conditioned medium (CM), also inducing the secretion of the SASP factor Interleukin-8 (IL-8). Here, we demonstrate the possibility to counteract both the autocrine senescence in LAM/TSC cells and senescence induced on PLFs by inhibiting CXCR2, an IL-8 receptor that controls the senescent response to IL-8 stimuli, through the small molecule SB225002. With the aim to deepen the composition of LAM/TSC CM to identify the factors involved in senescence process, we also demonstrate that LAM/TSC cells release sEVs that contribute to senescence spreading on PLFs. Interestingly, IL-8 is enriched in the LAM/TSC sEVs samples compared to PLFs. Taken together, our results indicate the therapeutic potential to interfere with senescence spreading in lung microenvironment and suggest the employment of molecules targeting senescence as a worthy pharmacological approach for LAM.
2026-06-05 | The Leiomyoma-LAM Convergence: Nrf2-Keap1-Cullin 3 Axis Hijacking, Selenium-Dependent GPx Exhaustion, and a Three-Tier Metabolic Governance Strategy Across Estrogen-Sensitive and mTOR-Driven Smooth Muscle Proliferation
This paper proposes that uterine leiomyomas and lymphangioleiomyomatosis (LAM) converge on a shared molecular vulnerability: persistent activation of Nrf2 as a stress-buffer rather than a stress-resolver. In leiomyomas, defective neddylation of the Cullin 3-RING E3 ligase complex locks Nrf2 in constitutive activation, buffering tumor cells against ROS from chronic hypoxia and estrogen-driven CYP1B1 activity. In LAM, constitutive mTORC1 activation drives Warburg-like metabolic overload forcing compensatory Nrf2 hyperactivation. In both, the selenoprotein infrastructure — GPx1, GPx4, and TrxR — is progressively exhausted by chronic Nrf2-driven synthesis demand that selenium-insufficient individuals cannot meet. A three-tier governance strategy is proposed: GLP-1 receptor agonism (systemic metabolic stabilization), selenium and mineral cofactor optimization (restoring GPx and TrxR capacity), and methylene blue (mitochondrial electron shuttle reducing the ROS load on the restored selenoprotein system). All claims are hypothesis-level requiring prospective clinical confirmation.
2026-06-03 | The SIK Axis as a Progression Modifier in Lymphangioleiomyomatosis: Nutritional Antioxidant Reserve as a Determinant of Healthy Tissue Survival in the TSC2-Driven Lung Microenvironment
Lymphangioleiomyomatosis is a rare, progressive, almost exclusively female lung disease driven by loss-of-function mutations in TSC2 genes, resulting in constitutive mTORC1 hyperactivation. This paper proposes that the SIK axis applies as a progression modifier in LAM — the rate at which healthy surrounding lung parenchymal cells survive the oxidative microenvironment created by LAM nodules is determined in part by their own selenium-dependent, NRF2-dependent, and CoQ10-dependent antioxidant reserve capacity. All claims are hypothesis-level requiring prospective investigation.
cell therapies
2026-06-26 | Decoding the Lymphangioleiomyomatosis (LAM) Niche Microenvironment via Integrative Analysis of Single Cell Multiomics and Spatial Transcriptomics.
Lymphangioleiomyomatosis (LAM) is a rare, destructive lung disease caused by mutations in TSC1 or TSC2, leading to mTORC1 hyperactivation. While mTOR inhibitor sirolimus, the only FDA approved drug for this disease, stabilizes lung function in most LAM patients, the drug does not eliminate LAM cells, underscoring a critical gap in our understanding of the tumor microenvironment and cellular heterogeneity that drive disease progression. This study provides the first comprehensive multiomics atlas of the human LAM niche, integrating single-cell/nucleus RNA-seq, single-nucleus ATAC-seq, and spatial transcriptomics to deconvolute its complex architecture. We elucidate LAM cellular heterogeneity by identifying three distinct subtypes: the canonical, uterine smooth muscle-like, mTORC1-hyperactive LAMCORE1; a novel, fibroblast-like LAMCORE2 subtype with potent extracellular matrix (ECM) remodeling activity; and LAMCORE3, a substate of LAMCORE1 that shares LAM and myogenic signatures but is characterized by a lower transcriptional activity and specific functional enrichment in protein translation.Our analysis reveals the transcriptomic heterogeneity of the LAM subtypes, orchestrated by distinct transcriptional drivers and networks. Furthermore, we uncover spatially resolved LAM-associated fibroblast (LAF) states, LAF-seed and LAF-niche, that orchestrate TGF-β signaling, ECM deposition and remodeling, and niche expansion. Spatial mapping uncovers a structured ecosystem where LAMCORE1 cells form a central core enmeshed with the lymphatic endothelium, which is surrounded by LAFs, LAMCORE2 cells, and reprogrammed immune and epithelial cells. Findings were validated through multimodal imaging technologies. Present work advances the field by providing the first high-resolution blueprint of the LAM niche microenvironment, revealing novel cell states and crosstalk that identify promising therapeutic targets.
2025-03-27 | Late living-donor kidney transplantation from the same donor after living-donor lobar lung transplantation.
Chronic kidney disease (CKD) is a common late complication associated with increased mortality after lung transplantation. Given the increased risk of infection in dialysis patients, late living-donor kidney transplantation (LDKT) provides excellent long-term survival in patients on dialysis after lung transplantation. However, recipients of living-donor lobar lung transplantation (LDLLT) might have scarce opportunity to receive LDKT due to the limited availability of living donors (LDs) for the second transplantation. We describe a successful case of late LDKT from the same donor after LDLLT. A 23-year-old woman with lymphangioleiomyomatosis underwent bilateral LDLLT of the right lower lobe from her brother and left lower lobe from her mother. Twelve years after LDLLT, she required hemodialysis for severe CKD. At the age of 37, she underwent LDKT from her mother, who was also an LD for the LDLLT. The postoperative courses of both the recipient and donor were uneventful, and the recipient remains in good physical condition (at the time of writing) despite developing recurrent lymphangioleiomyomatosis 23 years after the LDLLT, that is, 9 years after the LDKT. Her mother, the dual-organ LD, was able to return to her previous lifestyle. Late LDKT even from the same donor might be a viable option for patients developing severe CKD after LDLLT.
2024-08-08 | Single Lung Transplantation After Open Window Thoracotomy for Empyema: A Case Report.
A 41-year-old woman with lymphangioleiomyomatosis developed a bronchial anastomotic stenosis after left single lung transplantation (LTx). A part of the hyperinflated right native lung was excised in an attempt to remedy the left lung compression, which appeared to affect the bronchial anastomotic stenosis and ventilation/perfusion mismatch. However, a persistent air leak after the surgery caused empyema and an open window thoracotomy (OWT) was performed. She remained oxygen-dependent and was relisted for lung transplantation. A right single LTx on the side of OWT was performed, achieving long-term survival with no activity limitations for the patient. We report here the first successful LTx after OWT for empyema.
2020-10-19 | Adoptive T-Cell Transfer to Treat Lymphangioleiomyomatosis.
Patients with lymphangioleiomyomatosis (LAM) develop pulmonary cysts associated with neoplastic, smooth muscle-like cells that feature neuroendocrine cell markers. The disease preferentially affects premenopausal women. Existing therapeutics do not cure LAM. As gp100 is a diagnostic marker expressed by LAM lesions, we proposed to target this immunogenic glycoprotein using TCR transgenic T cells. To reproduce the genetic mutations underlying LAM, we cultured Tsc2-/- kidney tumor cells from aged Tsc2 heterozygous mice and generated a stable gp100-expressing cell line by lentiviral transduction. T cells were isolated from major histocompatibility complex-matched TCR transgenic pmel-1 mice to measure cytotoxicity in vitro, and 80% cytotoxicity was observed within 48 hours. Antigen-specific cytotoxicity was likewise observed using pmel-1 TCR-transduced mouse T cells, suggesting that transgenic T cells may likewise be useful to treat LAM in vivo. On intravenous injection, slow-growing gp100+ LAM-like cells formed lung nodules that were readily detectable in severe combined immunodeficient/beige mice. Adoptive transfer of gp100-reactive but not wild-type T cells into mice significantly shrunk established lung tumors, even in the absence of anti-PD-1 therapy. These results demonstrate the treatment potential of adoptively transferred T cells to eliminate pulmonary lesions in LAM.
2018-10-02 | Single lung transplantation for lymphangioleiomyomatosis: a single-center experience in Japan.
Lung transplantation is accepted as an effective modality for patients with end-stage pulmonary lymphangioleiomyomatosis (LAM). Generally, bilateral lung transplantation is preferred to single lung transplantation (SLT) for LAM because of native lung-related complications, such as pneumothorax and chylothorax. It remains controversial whether SLT is a suitable surgical option for LAM. The objective of this study was to evaluate the morbidity, mortality and outcome after SLT for LAM in a lung transplant center in Japan. We reviewed the records of 29 patients who underwent SLT for LAM in our hospital between March, 2000 and November, 2017. The data collected included the pre-transplant demographics of recipients, surgical characteristics, complications, morbidity, mortality and survival after SLT for LAM. The most common complication after SLT for LAM was contralateral pneumothorax (n = 7; 24.1%). Six of these recipients were treated successfully with chest-tube placement and none required surgery for the pneumothorax. The second-most common complication was chylous pleural effusion (n = 6; 20.7%) and these recipients were all successfully treated by pleurodesis. The 5-year survival rate after SLT for LAM was 79.5%. LAM-related complications after SLT for this disease can be managed. SLT is a treatment option and may improve access to lung transplantation for patients with end-stage LAM.
antibodies
2026-08-21 | T cell exhaustion in the peripheral blood of patients with sporadic lymphangioleiomyomatosis
Lymphangioleiomyomatosis (LAM) is a rare, progressive neoplastic lung disease. Lymphocytes play a central role in tumor immunity. However, circulating lymphocyte count and function have not been studied yet in sporadic LAM. Two-sample Mendelian randomization (TSMR) analysis was used to estimate the causal effect of circulating lymphocyte count on sporadic LAM. Circulating lymphocyte subsets were quantified, and inhibitory receptors (PD-1, LAG-3, TIM-3, and CTLA-4) on T cells were measured in a clinical cohort. CD4⁺ and CD8⁺ T cells were isolated and cultured to measure cytokine expression including IFN-γ and IL-4, followed by PD-1 blockade experiments using an anti-PD-1 antibody. TSMR analysis showed lower circulating lymphocyte count was associated with a higher risk of sporadic LAM. Circulating lymphocytes, mainly T cells instead of B and NK cells, were significantly decreased in sporadic LAM. Reduced CD8⁺ T cell count was significantly correlated with VEGF-D, CT gradings and FEV 1 % pred. The expression of PD-1, but not LAG-3, TIM-3, or CTLA-4, was significantly increased on both CD4⁺ and CD8⁺ T cells. The frequency of IFN-γ but not IL-4 producing CD4⁺ and CD8⁺ T cells was significantly decreased in sporadic LAM. PD-1 blockade restored the frequency of IFN-γ producing CD4⁺ and CD8⁺ T cells at least in part. Our data indicate that circulating lymphocytes, mainly T cells, are associated with the development of sporadic LAM. T cell exhaustion occurs in the peripheral blood of patients with this disease. Immune checkpoint blockade therapy may be a new strategy for sporadic LAM.
2025-10-31 | GPNMB immunohistochemistry is a useful ancillary tool for the diagnosis of pulmonary lymphangioleiomyomatosis.
Lymphangioleiomyomatosis (LAM) is a PEComa that primarily affects premenopausal women and is associated with the cystic destruction of the lung. Although smooth muscle and melanocytic markers can be helpful, histologic diagnosis of LAM remains challenging, especially in small biopsies. Glycoprotein non-metastatic melanoma protein B (GPNMB) expression has recently been identified as a highly specific and sensitive immunohistochemical marker for PEComas. Nevertheless, only a few LAM cases have been studied so far. The aim of this study was to assess the utility of GPNMB immunohistochemistry as an ancillary marker in a larger cohort of LAM samples. Immunohistochemistry for GPNMB was performed on cases of LAM (N = 15), potential differential diagnostic mimics (N = 30) and normal lung tissue (N = 2). Immunohistochemistry was assessed using the H-score method; an H-score above 100 was considered 'high'. All LAM cases showed strong cytoplasmic expression, with cell membrane accentuation in some areas. In contrast, differential diagnostic mimics were either negative or only weakly positive. Normal lung parenchyma was negative for GPNMB; however, weak-to-moderate expression was seen in alveolar macrophages in both the normal and diseased lung tissues in most cases. Considering only 'high' positivity, GPNMB immunohistochemistry showed 100% sensitivity and specificity for the diagnosis of LAM in our cohort. Based on its 100% sensitivity and specificity, GPNMB appears to be a highly valuable immunohistochemical marker for the diagnosis of pulmonary LAM. Besides its diagnostic value, the membrane positivity of GPNMB on LAM cells may predict a response to glembatumumab vedotin, an antibody-drug conjugate targeting GPNMB.
2024-10-01 | 9308 GPNMB Promotes Tumor Growth and is a Biomarker for Lymphangioleiomyomatosis (LAM)
Abstract Disclosure: E. Gibbons: None. M. Taya: None. H. Wu: None. S. Lopa: None. J. Moss: None. E.P. Henske: None. F.X. McCormack: None. S.R. Hammes: None. Lymphangioleiomyomatosis (LAM) is a rare, progressive cystic lung disease affecting almost exclusively female-sexed individuals. The cysts represent regions of lung destruction caused by smooth muscle tumors containing mutations in one of the two tuberous sclerosis (TSC) genes. mTORC1 inhibition slows but does not stop LAM advancement. Furthermore, monitoring disease progression is hindered by insufficient biomarkers. Therefore, new treatment options and biomarkers are needed. LAM cells express melanocytic markers, including Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB). The function of GPNMB in LAM is currently unknown; however, GPNMB’s unique cell surface expression on tumor versus benign cells makes GPNMB a potential therapeutic target, and persistent release of its extracellular ectodomain suggests potential as a serum biomarker. Here we establish that GPNMB regulates TSC2-null tumor cell invasion as well as TSC2-null xenograft tumor growth, and that GPNMB expression is dependent on mTORC1 signaling. Further, we show that GPNMB’s ectodomain is released from the cell surface of TSC2-null cells by ADAM10 and 17 proteases, and we identify the protease target sequence on GPNMB. In fact, mutating this cleavage sequence so that the GPNMB ectodomain can no longer be shed results in cessation of TSC2-null tumor growth. Finally, we demonstrate that GPNMB’s ectodomain is present at higher levels in LAM patient serum compared to healthy controls, and that ectodomain levels decrease with mTORC1 inhibition, making it a potential LAM biomarker. Presentation: 6/3/2024
2024-05-05 | mTOR dysregulation induces IL6 and paracrine AT2 cell senescence impeding lung repair in lymphangioleiomyomatosis
Abstract Lymphangioleiomyomatosis (LAM) is a rare disease which causes lung cysts and respiratory failure. TSC2 deficient ‘LAM cells’ with dysregulated mTOR signalling form nodules with fibroblasts causing lung injury. We examined if mTOR dysregulation could induce senescence and impair responses to lung injury. Senescence markers p21 and p16 were increased in LAM lungs and co-localised with alveolar type 2 cells. The SenMayo senescence gene panel was upregulated in LAM alveolar type 2 cells with senescence supressed by mTOR inhibition in patients. LAM cell / fibroblast spheroid cultures induced senescence markers in alveolar type 2 cell organoids, altered their growth and delayed epithelial scratch wound repair. Upstream regulator analysis predicted alveolar type 2 cell IL6 receptor activation. IL6 was produced by LAM cells, induced p16 and p21 in alveolar type 2 cells, inhibited epithelial wound resolution and was overexpressed in LAM patient serum where it was related to lung function. Wound repair in the presence of TSC2 null LAM cell / fibroblast spheroids was enhanced by the IL6 receptor antagonist Tocilizumab. Our findings show TSC2 loss induces senescence and IL6 production which are associated with impaired lung repair. Targeting IL6 signalling in parallel with mTOR inhibition, may reduce lung damage in LAM.
2023-10-01 | THU551 Glycoprotein-NMB (GPNMB) Is A Potential Lymphangioleiomyomatosis (LAM) Therapeutic Target And Biomarker
Abstract Disclosure: E. Gibbons: None. S.R. Hammes: None. Lymphangioleiomyomatosis (LAM) is a rare, progressive, destructive cystic lung disease affecting almost exclusively female-sexed individuals. Mutations in the tuberous sclerosis (TSC1 or TSC2) genes constitutively activate the mTORC1 pathway, promoting hyperproliferation of smooth muscle cells, creating small tumors throughout the lungs. These tumors, through largely unknown mechanisms, result in the formation of large cysts that replace normal alveolar space. Inhibition of mTORC1 with Sirolimus slows but does not stop LAM progression; therefore, there is a need for new LAM treatment options and biomarkers. Due to LAM’s estrogen sensitivity, female specificity, and metastatic nature, we previously proposed LAM cells originate from the uterine myometrium. We therefore designed a uterine-specific TSC2-null mouse model where all the mice generate uterine tumors characteristic of LAM and half develop lung metastases, suggesting that indeed LAM tumors may be derived from the uterus. Using bulk RNASeq analysis of uterine tissue from our mouse model, when focusing on genes regulated by estrogen and TSC2, we discovered increased expression of melanocytic markers, including Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB), a known oncogenic protein in other cancers. GPNMB was not only highly expressed in our mouse model; it was also expressed intracellularly and on the cell surface of TSC2-null cell lines and in LAM tumor cells from patient lungs and uteri. Notably, the extracellular domain of GPNMB was released from the surface of TSC2-null cell lines, suggesting that the ectodomain may also be released from TSC2-null cells in LAM patients. Here we show that, GPNMB protein and mRNA expression increased when the cells were serum starved, mimicking conditions of a tumor microenvironment. This increase was dependent on mTORC1 signaling and mRNA transcription. Knocking down GPNMB expression by siRNA had minimal effects on TSC2-null cells pro-tumorigenic functions in vitro aside from decreasing invasion. However, knocking out GPNMB in TSC2-null cells using CRISPR/Cas9 significantly decreased mouse xenograft tumor growth. Additionally, treating mice with a GPNMB antibody drug conjugate abrogated xenograft growth, highlighting GPNMB’s potential as a therapeutic target. Also, GPNMB’s ectodomain was released from the cell surface of TSC2-null cells by the proteases Adam10 and 17. Of note, the ectodomain is implicated in mediating GPNMB’s effects on tumor growth, suggesting that Adam10/17 inhibition may mitigate TSC2-null tumor growth. Importantly, the GPNMB ectodomain is a potential serum biomarker of LAM, as there was a significant increase in GPNMB ectodomain levels in patient serum as compared with healthy controls. Furthermore, serum GPNMB levels decreased in most patients after Sirolimus treatment, implicating GPNMB as a potential marker for responsiveness to treatment. Presentation: Thursday, June 15, 2023
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2025-05-01 | Neural Crest Markers Are Therapeutic Targets for Tuberous Sclerosis and Lymphangioleiomyomatosis Neoplasms
Abstract RATIONALE: The hypothesis regarding the neural crest origin of TSC (tuberous sclerosis complex) and LAM (lymphangioleiomyomatosis) tumors has generated considerable debate. This is based on the mesenchymal phenotypes of these neoplasms and their occurrence in areas of the body that are known ontogenetic destinations for maturing neural crest cells. However, this hypothesis has not been thoroughly evaluated, limiting the potential for developing therapies that target tumorigenic neural crest cells (NCCs) and their mesenchymal derivatives. METHODS: We analyzed single-cell populations from renal cortical tissues of the B6129SF2/J wildtype mice (N=3 mice; 19078 cells) and renal cystadenomas in Tsc2+/- mice (N=4 mice; 26861 cells) used as an animal model of TSC. Distinct NCC subpopulations were identified in renal tumors based on their significant expression of 40 neural crest markers. Differential gene expression and signaling pathway analyses were performed on tumorigenic NCCs, with validation in Tsc2+/- mice and LAM tumors via immunohistochemistry, western blotting, and RT-qPCR. We employed CRISPR/Cas9 to generate knockout mouse cranial NCC lines targeting the neuro-immunomodulatory marker osteopontin (Spp1) and assessed the tumorigenic potential of Spp1WT vs. Spp1KO NCCs through migration, invasion, proliferation, and viability assays. RESULTS: Tumorigenic cranial neural crest cells constituted 0.6% of the dissociated tumor cells from the Tsc2+/- mice, representing an 80-fold increase compared to wild-type mice renal tissue. The NCCs in Tsc2+/- mice renal tumors expressed gene signatures indicating transformation, and that are distinct from endogenous immune cells and renal tissue, including secreted phosphoprotein 1 (Spp1), Clusterin (Clu), SRY-box 9 (Sox9), Lipocalin-2 (Lcn2), and cytokeratin 18 (Krt18). The expression of select tumorigenic NCC markers was validated in Tsc2+/- mice renal and hepatic tumors, pulmonary LAM lesions, and renal angiomyolipoma but not in age-matched healthy tissues. Notably, the expression levels of these tumorigenic NCC markers increased with the age of Tsc2+/- tumors, from 6 to 16 months. Knockout of Spp1 significantly reduced NCC invasion (87%), migration (92%), and proliferation (63%) without affecting cell viability. CONCLUSION: Cranial neural crest cells present in wildtype mice kidneys genetically transform and proliferate in Tsc2+/- mice, leading to renal cystadenomas. This study characterizes these tumorigenic cranial NCCs in the Tsc2+/-mice and highlights the crucial role of secreted phosphoprotein Spp1 in their transformation into tumors and as a potential therapeutic for LAM and TSC tumors. Future research will explore the therapeutic potential of other tumorigenic NCC markers resolved in our study and investigate the regulatory mechanisms driving NCC transformation.
2024-07-11 | Plasmacytoid Dendritic Cells Mediate CpG-ODN-induced Increase in Survival in a Mouse Model of Lymphangioleiomyomatosis.
Lymphangioleiomyomatosis (LAM) is a devastating disease primarily found in women of reproductive age that leads to cystic destruction of the lungs. Recent work has shown that LAM causes immunosuppression and that checkpoint inhibitors can be used as LAM treatment. Toll-like receptor (TLR) agonists can also reactivate immunity, and the TLR9 agonist CpG oligodeoxynucleotide (CpG-ODN) has been effective in treating lung cancer in animal models. In this study, we investigated the use of TLR9 agonist CpG-ODN as LAM immunotherapy in combination with checkpoint inhibitor anti-PD1 and standard of care rapamycin, and determined the immune mechanisms underlying therapeutic efficacy. We used survival studies, flow cytometry, ELISA, and histology to assess immune response and survival after intranasal treatment with CpG-ODN in combination with rapamycin or anti-PD1 therapy in a mouse model of metastatic LAM. We found that local administration of CpG-ODN enhances survival in a mouse model of LAM. We found that a lower dose led to longer survival, likely because of fewer local side effects, but increased LAM nodule count and size compared with the higher dose. CpG-ODN treatment also reduced regulatory T cells and increased the number of T-helper type 17 cells as well as cytotoxic T cells. These effects appear to be mediated in part by plasmacytoid dendritic cells because depletion of plasmacytoid dendritic cells reduces survival and abrogates T-helper type 17 cell response. Finally, we found that CpG-ODN treatment is effective in early-stage and progressive disease and is additive with anti-PD1 therapy and rapamycin. In summary, we have found that TLR9 agonist CpG-ODN can be used as LAM immunotherapy and effectively synergizes with rapamycin and anti-PD1 therapy in LAM.
2023-02-07 | Inhaled CpG increases survival and synergizes with checkpoint inhibition in lymphangioleiomyomatosis
ABSTRACT Lymphangioleiomyomatosis (LAM) is a devastating disease primarily found in women of reproductive age that leads to cystic destruction of the lungs. Recent work has shown that LAM causes immunosuppression and that checkpoint inhibitors can be used as LAM treatment. Toll-like receptor (TLR) agonists can also re-activate immunity and the TLR9 agonist, CpG-ODN, has been effective in treating lung cancer in animal models. Here we investigate the use of TLR9 agonist CpG-ODN as LAM immunotherapy in combination with checkpoint inhibitor, anti-PD1, standard of care rapamycin and determine the immune mechanisms underlying therapeutic efficacy. We used survival studies, flow cytometry, ELISA, and histology to assess immune response and survival after intranasal treatment with CpG-ODN in combination with rapamycin or anti-PD1 therapy in a mouse model of metastatic LAM. We found that local administration of CpG-ODN enhances survival in a mouse model of LAM. We found that a lower dose led to longer survival likely due to fewer local side effects but increased LAM nodule count and size compared to the higher dose. CpG-ODN treatment also reduced regulatory T cells and increased the number of Th17 helper T cells as well as cytotoxic T cells. These effects appear to be mediated in part by plasmacytoid dendritic cells (pDCs), as depletion of pDCs reduces survival and abrogates Th17 T cell response. Finally, we found that CpG-ODN treatment is effective in early stage and progressive disease and is additive with anti-PD1 therapy and rapamycin. In summary, we have found that TLR9 agonist CpG-ODN can be used as LAM immunotherapy and effectively synergizes with rapamycin and anti-PD1 therapy in LAM.
2022-03-14 | Lung-selective mRNA delivery of synthetic lipid nanoparticles for the treatment of pulmonary lymphangioleiomyomatosis.
Safe and efficacious systemic delivery of messenger RNA (mRNA) to specific organs and cells in vivo remains the major challenge in the development of mRNA-based therapeutics. Targeting of systemically administered lipid nanoparticles (LNPs) coformulated with mRNA has largely been confined to the liver and spleen. Using a library screening approach, we identified that N-series LNPs (containing an amide bond in the tail) are capable of selectively delivering mRNA to the mouse lung, in contrast to our previous discovery that O-series LNPs (containing an ester bond in the tail) that tend to deliver mRNA to the liver. We analyzed the protein corona on the liver- and lung-targeted LNPs using liquid chromatography-mass spectrometry and identified a group of unique plasma proteins specifically absorbed onto the surface that may contribute to the targetability of these LNPs. Different pulmonary cell types can also be targeted by simply tuning the headgroup structure of N-series LNPs. Importantly, we demonstrate here the success of LNP-based RNA therapy in a preclinical model of lymphangioleiomyomatosis (LAM), a destructive lung disease caused by loss-of-function mutations in the Tsc2 gene. Our lung-targeting LNP exhibited highly efficient delivery of the mouse tuberous sclerosis complex 2 (Tsc2) mRNA for the restoration of TSC2 tumor suppressor in tumor and achieved remarkable therapeutic effect in reducing tumor burden. This research establishes mRNA LNPs as a promising therapeutic intervention for the treatment of LAM.
2021-12-23 | The microRNA miR-132 is a key regulator of lymphatic vascular remodelling
ABSTRACT Lymphangiogenesis (growth of new lymphatic vessels), and lymphatic remodelling more broadly, are important for disease progression in cancer, lymphedema and the pulmonary disease lymphangioleiomyomatosis. Multiple molecular pathways which signal for aspects of lymphangiogenesis are known but little is understood about their co-ordinate regulation in lymphatic endothelial cells (LECs). Small RNA molecules co-ordinately regulate complex biological processes, but knowledge about their involvement in lymphangiogenesis is limited. Here we used high-throughput small RNA sequencing of LECs to identify microRNAs (miRs) regulating lymphatic remodelling driven by the lymphangiogenic growth factors VEGF-C and VEGF-D. We identified miR-132 as up-regulated by both growth factors, and demonstrated that inhibiting miR-132 in LECs in vitro blocked cell proliferation and tube formation, key steps in lymphangiogenesis. We showed that miR-132 is expressed in human LECs in vivo in the lymphatics of human breast tumours expressing VEGF-D. Importantly, we demonstrated that inhibiting miR-132 in vivo blocked many aspects of lymphangiogenesis in mice. Finally, we identified mRNAs regulated by miR-132 in LECs, by sequencing after RNA-protein cross-linking and Argonaute immunoprecipitation, which demonstrated how miR-132 co-ordinately regulates signalling pathways in lymphangiogenesis. This study shows miR-132 is a critical regulator of lymphangiogenesis and a potential target for therapeutically manipulating lymphatic remodelling in disease.
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Drug Discovery Landscape
5 orphan drug designations for Lymphangioleiomyomatosis, including 1 approved therapy.
5 orphan drug designations for Lymphangioleiomyomatosis, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Sirolimus | small molecules | EMA | Maxia Strategies-Europe Limited | |
sirolimus | small molecules | FDA | Cote Orphan Consulting, LLC | |
sirolimus | small molecules | FDA | LAM Therapeutics, Inc. | |
sirolimus [Rapamune] | small molecules | FDA | Approved | Pfizer, Inc. |
Quinacrine hydrochloride | small molecules | FDA | — | Lyphomed, Inc. |
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