Leca Julie, Martinez Sébastien, Lac Sophie, Nigri Jérémy, Secq Véronique, Rubis Marion, Bressy Christian, Sergé Arnauld, Lavaut Marie-Noelle, Dusetti Nelson, Loncle Céline, Roques Julie, Pietrasz Daniel, Bousquet Corinne, Garcia Stéphane, Granjeaud Samuel, Ouaissi Mehdi, Bachet Jean Baptiste, Brun Christine, Iovanna Juan L, Zimmermann Pascale, Vasseur Sophie, Tomasini Richard
J Clin Invest. 2016 Nov 1;126(11):4140-4156. doi: 10.1172/JCI87734. Epub 2016 Oct 4.
The intratumoral microenvironment, or stroma, is of major importance in the pathobiology of pancreatic ductal adenocarcinoma (PDA), and specific conditions in the stroma may promote increased cancer aggressiveness. We hypothesized that this heterogeneous and evolving compartment drastically influences tumor cell abilities, which in turn influences PDA aggressiveness through crosstalk that is mediated by extracellular vesicles (EVs). Here, we have analyzed the PDA proteomic stromal signature and identified a contribution of the annexin A6/LDL receptor-related protein 1/thrombospondin 1 (ANXA6/LRP1/TSP1) complex in tumor cell crosstalk. Formation of the ANXA6/LRP1/TSP1 complex was restricted to cancer-associated fibroblasts (CAFs) and required physiopathologic culture conditions that improved tumor cell survival and migration. Increased PDA aggressiveness was dependent on tumor cell-mediated uptake of CAF-derived ANXA6+ EVs carrying the ANXA6/LRP1/TSP1 complex. Depletion of ANXA6 in CAFs impaired complex formation and subsequently impaired PDA and metastasis occurrence, while injection of CAF-derived ANXA6+ EVs enhanced tumorigenesis. We found that the presence of ANXA6+ EVs in serum was restricted to PDA patients and represents a potential biomarker for PDA grade. These findings suggest that CAF-tumor cell crosstalk supported by ANXA6+ EVs is predictive of PDA aggressiveness, highlighting a therapeutic target and potential biomarker for PDA.
肿瘤内微环境，即基质，在胰腺导管腺癌（PDA）的病理生物学中至关重要，基质中的特定条件可能会促进癌症侵袭性增加。我们假设这个异质性且不断演变的区域会极大地影响肿瘤细胞的能力，进而通过细胞外囊泡（EVs）介导的相互作用影响PDA的侵袭性。在这里，我们分析了PDA蛋白质组学基质特征，并确定了膜联蛋白A6/低密度脂蛋白受体相关蛋白1/血小板反应蛋白1（ANXA6/LRP1/TSP1）复合物在肿瘤细胞相互作用中的作用。ANXA6/LRP1/TSP1复合物的形成仅限于癌症相关成纤维细胞（CAFs），并且需要改善肿瘤细胞存活和迁移的生理病理培养条件。PDA侵袭性增加依赖于肿瘤细胞介导的摄取携带ANXA6/LRP1/TSP1复合物的CAF衍生的ANXA6+ EVs。CAFs中ANXA6的缺失会损害复合物的形成，随后损害PDA和转移的发生，而注射CAF衍生的ANXA6+ EVs会增强肿瘤发生。我们发现血清中ANXA6+ EVs的存在仅限于PDA患者，并且代表了PDA分级的潜在生物标志物。这些发现表明，由ANXA6+ EVs支持的CAF-肿瘤细胞相互作用可预测PDA的侵袭性，突出了PDA的治疗靶点和潜在生物标志物。
