Cancer-associated fibroblast-derived annexin A6+ extracellular vesicles support pancreatic cancer aggressiveness
Julie Leca, Sébastien Martinez, Sophie Lac, Jérémy Nigri, Véronique Secq, Marion Rubis, Christian Bressy, Arnauld Sergé, Marie-Noelle Lavaut, Nelson Dusetti, Céline Loncle, Julie Roques, Daniel Pietrasz, Corinne Bousquet, Stéphane Garcia, Samuel Granjeaud, Mehdi Ouaissi, Jean Baptiste Bachet, Christine Brun, Juan L. Iovanna, Pascale Zimmermann, Sophie Vasseur, Richard Tomasini
Julie Leca, Sébastien Martinez, Sophie Lac, Jérémy Nigri, Véronique Secq, Marion Rubis, Christian Bressy, Arnauld Sergé, Marie-Noelle Lavaut, Nelson Dusetti, Céline Loncle, Julie Roques, Daniel Pietrasz, Corinne Bousquet, Stéphane Garcia, Samuel Granjeaud, Mehdi Ouaissi, Jean Baptiste Bachet, Christine Brun, Juan L. Iovanna, Pascale Zimmermann, Sophie Vasseur, Richard Tomasini
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Research Article Cell biology Oncology

Cancer-associated fibroblast-derived annexin A6+ extracellular vesicles support pancreatic cancer aggressiveness

Abstract

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.

Authors

Julie Leca, Sébastien Martinez, Sophie Lac, Jérémy Nigri, Véronique Secq, Marion Rubis, Christian Bressy, Arnauld Sergé, Marie-Noelle Lavaut, Nelson Dusetti, Céline Loncle, Julie Roques, Daniel Pietrasz, Corinne Bousquet, Stéphane Garcia, Samuel Granjeaud, Mehdi Ouaissi, Jean Baptiste Bachet, Christine Brun, Juan L. Iovanna, Pascale Zimmermann, Sophie Vasseur, Richard Tomasini

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Figure 6

ANXA6+ EVs are a biomarker for pancreatic cancer.

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ANXA6+ EVs are a biomarker for pancreatic cancer. (A) Quantification of ...
(A) Quantification of ANXA6+ EVs purified from serum obtained from healthy donors (n = 30, as baseline), patients with benign pancreatic disease (n = 14), patients with PDA (n = 108), and those with other cancers (n = 11) (median ± interquartile range). **P < 0.01, ***P < 0.001, Mann-Whitney U test. (B) Quantification of circulating ANXA6+ EVs obtained from healthy donors (n = 30, as baseline) and PDA patients with grade 1 (resectable, n = 18), grade 2 (nonresectable and locally advanced, n = 29), and grade 3 (n = 53, nonresectable and metastatic) (median ± interquartile range). *P < 0.05, **P < 0.01, ***P < 0.001, Wilcoxon test. (C) Kaplan-Meier overall survival curves for PDA patients with grade 1 (resectable, n = 18), grade 2 (nonresectable and locally advanced, n = 29), and grade 3 (n = 53, nonresectable and metastatic). (D) Receiver operating characteristic curve analyses of CA 19-9, with AUC = 0.928, and ANXA6, with AUC = 0.979. Analysis realized on 27 healthy donors and 78 patients with PDA. (E) Linear regression of ANXA6 versus vimentin expression level using transcriptomic analysis on patient-derived xenografts (n = 60). Dashed lines represent 95% CI. (F) Kaplan-Meier survival curve using transcriptomic analysis on patient-derived xenografts, divided into high (>373) and low (<373) ANXA6 expression groups based on the log-rank statistic test (n = 10 and n = 50, respectively). P = 0.0003. (G) Decision tree using transcriptomic analysis on patient-derived xenografts (n = 60). First node is based on ANXA6 level (>377, n = 10, or <377, n = 50), second on α-SMA level (>58.5, n = 18, or <58.5, n = 32), third on LRP1 level (>946, n = 17, or <946, n = 15).