Dataset Information

Extracellular vesicles from pancreatic cancer cells activate mast cells which in turn promote tumor cell proliferation and establish a tumor-supportive microenvironment

ABSTRACT: Background and aim: Recent studies reveal a critical role of tumor cell-released extracellular vesicles (EVs) in pancreatic cancer progression. Driver genes directing EV function, the EV-recipient cells, as well as their cellular response to EV uptake remain, however, to be identified. To address this, we investigated the role of the EV biogenesis regulator Bcl-2-associated-anthanogene6 (BAG6)for cancer progression. Methods: We 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 preclinical mouse models for pancreatic ductal adenocarcinoma (PDAC) in a Bag6 pro- or deficient background. In vivo data were validated using mouse and human organoids, as well aspatient samples. Results: Bag6-deficient subcutaneous and orthotopic PDAC tumors showed accelerated tumor growth dependent on EV release. Mechanistically, this was attributed to mast cell (MC) activation via EV-associate IL33. Activated MCs promoted tumor cell proliferation and altered the composition of the TME affecting fibroblast polarization and immune cell infiltration. Tumor cell proliferation and TME remodeling were mediated via the MC secretome containing high levels of PDGF and CD73. In patients, BAG6 gene expression and protein serum level correlated with survival and low MC infiltration indicating clinical relevance. Conclusion: The study revealed a tumor-suppressing activity of BAG6 in PDAC, unknown up to now. Bag6-deficiency allowed the release of Evs-associated IL33 which shaped the composition of the TME via MC activation causing aggressive tumor growth. MC depletion using Imatinib diminished tumor growth providing a scientific rationale for the evaluation of Imatinib treatment of patients stratified for low BAG6 expression and high MC infiltration.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Elke Pogge von Strandmann

PROVIDER: MSV000093583 | MassIVE | Wed Dec 06 01:20:00 GMT 2023

SECONDARY ACCESSION(S): PXD047563

REPOSITORIES: MassIVE

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Publications

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

Alashkar Alhamwe Bilal B Ponath Viviane V Alhamdan Fahd F Dörsam Bastian B Landwehr Clara C Linder Manuel M Pauck Kim K Miethe Sarah S Garn Holger H Finkernagel Florian F Brichkina Anna A Lauth Matthias M Tiwari Dinesh Kumar DK Buchholz Malte M Bachurski Daniel D Elmshäuser Sabrina S Nist Andrea A Stiewe Thorsten T Pogge von Strandmann Lisa L Szymański Witold W Beutgen Vanessa V Graumann Johannes J Teply-Szymanski Julia J Keber Corinna C Denkert Carsten C Jacob Ralf R Preußer Christian C Pogge von Strandmann Elke E

Cellular & molecular immunology 20240628 8

Recent studies reveal a critical role of tumor cell-released extracellular vesicles (EVs) in pancreatic cancer (PC) progression. However, driver genes that direct EV function, the EV-recipient cells, and their cellular response to EV uptake remain to be identified. Therefore, we studied the role of Bcl-2-associated-anthanogene 6 (BAG6), a regulator of EV biogenesis for cancer progression. We used a Cre recombinase/LoxP-based reporter system in combination with single-cell RNA sequencing to monit ...[more]

PMID: 38942797

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