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Abstract：
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. EVs derived from BAG6-deficient pancreatic cancer cells induce MC activation via IL33/Il1rl1. The secretome of activated MCs induces tumor proliferation and changes in the TME, particularly shifting fibroblasts into an inflammatory cancer-associated fibroblast (iCAF) phenotype. Blocking EVs or depleting MCs restricts tumor growth.
摘要：
最近的研究揭示了肿瘤细胞释放的细胞外囊泡（EV）在胰腺癌（PC）进展中的关键作用。然而,指导EV功能的驱动基因，EV受体细胞，它们对EV摄取的细胞反应仍有待鉴定。因此,我们研究了Bcl-2相关花序花序6（BAG6）的作用，癌症进展的EV生物发生调节剂。我们使用基于Cre重组酶/LoxP的报告系统与单细胞RNA测序相结合，以监测Bag6前或缺陷背景下胰腺导管腺癌（PDAC）小鼠模型的体内EV摄取和肿瘤微环境（TME）变化。使用小鼠和人类类器官和患者样品验证体内数据。我们的数据表明，Bag6缺陷的皮下和原位PDAC肿瘤加速了肿瘤的生长，这取决于EV的释放。机械上,这归因于通过EV相关IL33激活肥大细胞(MC).活化的MC促进肿瘤细胞增殖并改变TME的组成，影响成纤维细胞极化和免疫细胞浸润。肿瘤细胞增殖和成纤维细胞极化是通过含有高水平PDGF和CD73的MC分泌组介导的。具有高BAG6基因表达和高蛋白血浆水平的患者具有更长的总生存期,表明临床相关性。目前的研究揭示了迄今为止未知的BAG6在PDAC中的肿瘤抑制活性。Bag6缺乏症允许释放与EV相关的IL33，该IL33通过MC激活促进侵袭性肿瘤生长来调节TME。使用伊马替尼的MC耗竭减少了肿瘤生长，为将伊马替尼用于BAG6低表达和MC高浸润分层的患者提供了科学依据。源自BAG6缺陷型胰腺癌细胞的EV通过IL33/Il1rl1诱导MC活化。激活的MCs的分泌组诱导肿瘤增殖和TME的变化，特别是将成纤维细胞转变为炎性癌症相关成纤维细胞（iCAF）表型。阻断EV或耗尽MC会限制肿瘤生长。
