2026-07-09 | An Integrative RNA Spliceosomic Landscape of Pancreatic Neuroendocrine Tumors Identifies Clinically Relevant Molecular Subgroups.

Alterations in alternative splicing are emerging as a novel cancer hallmark, offering new insights into tumor biology. However, integrative analyses of splicing are still scarce, particularly in rare cancers like pancreatic neuroendocrine tumors (PanNETs), whose striking heterogeneity complicates patient diagnosis and treatment. Here, we provide the first comprehensive characterization of the RNA splicing landscape in PanNETs through integrative analysis of RNA-seq data from 174 tumor samples. We identified three robust spliceosomic groups (SPN1, SPN2, SPN3) each associated with unique clinical and molecular characteristics. SPN1 displayed intermediate clinical behavior alongside enhanced mTOR signaling; SPN2 was characterized by a less secretory phenotype, enrichment in alpha-cell markers and somatostatin receptors, increased metastasis, and frequent mutations in MEN1 and DAXX/ATRX genes; in contrast, SPN3 was composed mainly by low grade tumors with beta-cell marker expression and the lowest mutational rate, yet it also contained all the highly proliferative neoplasms. Moreover, each group had a specific alternative splicing events signature, revealing an unprecedented discovery: the association between the expression profile of the splicing machinery and its product, the splicing variants. We provide a detailed characterization of the molecular and functional consequences of the splice variants defining each of the spliceosomic groups. These findings underscore the previously unrecognized yet significant impact of RNA splicing on PanNET heterogeneity and suggest that detailed splicing profiles could serve as valuable tools for identifying novel biomarkers and therapeutic targets. Thus, beyond providing crucial insights into PanNET molecular biology, our study offers a foundation for future studies exploring personalized therapeutic strategies based on splicing features.

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2026-07-08 | Long term survival in three pancreatic cancer patients following Whipple's procedure and allogeneic hematopoietic cell transplantation.

Pancreatic ductal adenocarcinoma (PDAC) is associated with an extremely poor prognosis, with long-term survival being exceedingly rare. Here, we follow-up on three long-term survivors. This study initially included eight patients with PDAC who underwent radical resection via Whipple's procedure with no evidence of distant metastases. Two of these patients received allogeneic hematopoietic cell transplantation (HCT) in a previously published trial. The remaining six patients, who served as controls and did not receive HCT, died of progressive PDAC within one to four years. Additionally, a 60-year-old male with PDAC who underwent partial pancreatectomy and gastrectomy received HCT from a matched unrelated donor. Patient 1 developed mild acute graft-versus-host disease (GVHD) of the skin, followed by chronic GVHD. He subsequently underwent surgery for oral cancer and remains alive 21 years after the initial PDAC diagnosis, with no evidence of recurrence. Patient 2 experienced severe acute gastrointestinal GVHD and recurrent chronic bronchiolitis obliterans. He died of esophageal cancer 19 years after PDAC diagnosis. Patient 3 experienced graft rejection and multiple medical complications, including radical surgery for colorectal cancer, yet remains cancer-free 15 years after PDAC diagnosis. In conclusion, HCT may confer anticancer effects in patients with radically resected PDAC. Further investigations are warranted to confirm its therapeutic value.ClinicalTrials.gov Identifier: NCT02207985.

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2026-07-01 | Transcriptomic-based molecular classification of ampullary adenocarcinoma.

Ampullary adenocarcinoma (AMPAC) is a rare and heterogeneous malignancy with markedly variable clinical outcomes, underscoring the urgent need for molecularly informed classification and personalized therapeutic strategies. Current AMPAC classification relies primarily on morphological and immunohistochemical criteria, which lack prognostic accuracy and fail to capture the underlying molecular and tumor microenvironment heterogeneity. In this study, we integrated bulk RNA sequencing, single-cell RNA sequencing (scRNA-seq), and clinicopathological data to elucidate the molecular architecture of AMPAC and introduced a transcriptomic-based molecular classification (AMS). The AMS categorized patients into two molecular subtypes: mesenchymal AMPAC (AMS-M) and classical AMPAC (AMS-C). The AMS-M demonstrated increased epithelial-mesenchymal transition (EMT) and stromal activation, correlating with basal-like subtypes associated with unfavorable prognosis. In contrast, AMS-C tumors exhibited metabolic and differentiation programs with relatively preserved immune infiltration. Importantly, we identified MUC16 as a pivotal biomarker specifically overexpressed in AMS-M tumors. MUC16 knockout markedly reversed EMT, attenuated invasive and migratory capacities, and restored chemosensitivity in both cell lines and their xenograft models. Collectively, our findings establish AMS as a prognostically and therapeutically informative molecular classification framework for AMPAC, unveil the critical role of the tumor microenvironment in AMPAC heterogeneity, and provide a translational foundation for precision oncology in this rare tumor.

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