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 respon...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 monitor in vivo EV uptake and tumor microenvironment(TME)changes in mouse models for pancreatic ductal adenocarcinoma(PDAC)in a Bag6 pro-or deficient background.In vivo data were validated using mouse and human organoids and patient samples.Our data demonstrated that Bag6-deficient subcutaneous and orthotopic PDAC tumors accelerated tumor growth dependent on EV release.Mechanistically,this was attributed to mast cell(MC)activation via EV-associated 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 fibroblast polarization were mediated via the MC secretome containing high levels of PDGF and CD73.Patients with high BAG6 gene expression and high protein plasma level have a longer overall survival indicating clinical relevance.The current study revealed a so far unknown tumor-suppressing activity of BAG6 in PDAC.Bag6-deficiency allowed the release of EV-associated IL33 which modulate the TME via MC activation promoting aggressive tumor growth.MC depletion using imatinib diminished tumor growth providing a scientific rationale to consider imatinib for patients stratified with low BAG6 expression and high MC infiltration.展开更多
基金This work was supported by grants from Deutsche Forschungsgemeinschaft(KFO325,project 329116008 and GRK2573,project 416910386 to EPvS)Hessisches Ministerium fur Wissenschaft und Kunst(LOEWE iCANx to EPvS)+1 种基金from von Behring-RontgenStiftung(66-0024 to VP and BD)Open Access funding enabled and organized by Projekt DEAL.
文摘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 monitor in vivo EV uptake and tumor microenvironment(TME)changes in mouse models for pancreatic ductal adenocarcinoma(PDAC)in a Bag6 pro-or deficient background.In vivo data were validated using mouse and human organoids and patient samples.Our data demonstrated that Bag6-deficient subcutaneous and orthotopic PDAC tumors accelerated tumor growth dependent on EV release.Mechanistically,this was attributed to mast cell(MC)activation via EV-associated 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 fibroblast polarization were mediated via the MC secretome containing high levels of PDGF and CD73.Patients with high BAG6 gene expression and high protein plasma level have a longer overall survival indicating clinical relevance.The current study revealed a so far unknown tumor-suppressing activity of BAG6 in PDAC.Bag6-deficiency allowed the release of EV-associated IL33 which modulate the TME via MC activation promoting aggressive tumor growth.MC depletion using imatinib diminished tumor growth providing a scientific rationale to consider imatinib for patients stratified with low BAG6 expression and high MC infiltration.
