MassIVE MSV000093583

Partial Public PXD047563

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

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Description

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. [doi:10.25345/C58P5VM5M] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: extracellular vesicles ; mouse ; pancreatic cancer ; TimsTof Pro ; DDA ; Bag6

Contact

Principal Investigators:
(in alphabetical order) 		Elke Pogge von Strandmann, Institute for Tumor Immunology, Philipps-University Marburg, Germany
Submitting User: Wszymanski

Publications

Alashkar Alhamwe B, Ponath V, Alhamdan F, Dörsam B, Landwehr C, Linder M, Pauck K, Miethe S, Garn H, Finkernagel F, Brichkina A, Lauth M, Tiwari DK, Buchholz M, Bachurski D, Elmshäuser S, Nist A, Stiewe T, Pogge von Strandmann L, Szyma?ski W, Beutgen V, Graumann J, Teply-Szymanski J, Keber C, Denkert C, Jacob R, Preußer C, Pogge von Strandmann E.
BAG6 restricts pancreatic cancer progression by suppressing the release of IL33-presenting extracellular vesicles and the activation of mast cells.
Cell Mol Immunol. 2024 Aug;21(8):918-931. Epub 2024 Jun 28.

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