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BAG6 restricts pancreatic cancer progression by suppressing the release of IL33-presenting extracellular vesicles and the activation of mast cells

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Cellular & Molecular Immunology 2024年第8期21卷 918-931页

作者： Bilal Alashkar Alhamwe Viviane Ponath fahd alhamdan Bastian Dörsam Clara Landwehr Manuel Linder Kim Pauck Sarah Miethe Holger Garn Florian Finkernagel Anna Brichkina Matthias Lauth Dinesh Kumar Tiwari Malte Buchholz Daniel Bachurski Sabrina Elmshäuser Andrea Nist Thorsten Stiewe Lisa Pogge von Strandmann Witold Szymański Vanessa Beutgen Johannes Graumann Julia Teply-Szymanski Corinna Keber Carsten Denkert Ralf Jacob Christian Preußer Elke Pogge von Strandmann Institute for Tumor Immunology Philipps-University35043MarburgGermany Core Facility Extracellular Vesicles Philipps-University35043MarburgGermany Department of Anesthesiology Critical Careand Pain MedicineCardiac Anesthesia DivisionBoston Children’s HospitalBostonUSA Department of Immunology and Anaesthesia Harvard Medical SchoolBostonMAUSA Translational Inflammation Research Division&Core Facility for Single Cell Multiomics Philipps-University35043MarburgGermany Core Facility Bioinformatics Philipps-University35043MarburgGermany Clinic for Gastroenterology Endocrinology and MetabolismCenter for Tumor and Immune BiologyPhilipps-University35043MarburgGermany Institute of Systems Immunology Philipps-University35043MarburgGermany Cluster of Excellence on Cellular Stress Responses in Aging-Associated Diseases(CECAD) University of CologneCologneGermany Institute of Molecular Oncology and Genomics Core Facility Member of the German Center for Lung Research(DZL)Philipps-University35043MarburgGermany Institute of Lung Health Justus Liebig University35392GiessenGermany Institute of Translational Proteomics&Core Facility Translational Proteomics Biochemical/Pharmacological CentrePhilipps-University35043MarburgGermany Institute of Pathology Philipps-University Marburg and University Hospital Marburg(UKGM)MarburgGermany Department of Cell Biology and Cell Pathology Philipps-University35043MarburgGermany

Recent studies reveal a critical role of tumor cell-released extracellular vesicles(EVs)in pancreatic cancer(PC)***,driver genes that direct EV function,the EV-recipient cells,and their cellular response to EV uptake remain to be ***,we studied the role of Bcl-2-associated-anthanogene 6(BAG6),a regulator of EV biogenesis for cancer *** used a Cre recombinase/LoxP-based reporter system in combination with single-cell RNA sequencing to monitor in vivo EV uptake and tumor microenvironment(TME)changes in mouse models for pancreatic ductal adenocarcinoma(PDAC)in a Bag6 pro-or deficient *** vivo data were validated using mouse and human organoids and patient *** data demonstrated that Bag6-deficient subcutaneous and orthotopic PDAC tumors accelerated tumor growth dependent on EV ***,this was attributed to mast cell(MC)activation via EV-associated *** MCs promoted tumor cell proliferation and altered the composition of the TME affecting fibroblast polarization and immune cell *** cell proliferation and fibroblast polarization were mediated via the MC secretome containing high levels of PDGF and *** with high BAG6 gene expression and high protein plasma level have a longer overall survival indicating clinical *** current study revealed a so far unknown tumor-suppressing activity of BAG6 in ***6-deficiency allowed the release of EV-associated IL33 which modulate the TME via MC activation promoting aggressive tumor *** depletion using imatinib diminished tumor growth providing a scientific rationale to consider imatinib for patients stratified with low BAG6 expression and high MC infiltration.

关键词： Pancreatic cancer EVs BAG6 Mast cells

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