Abstract A61: CAF-derived ANXA6+-exosomes support pancreatic cancer aggressiveness and serve as a circulating biomarker

Abstract Pancreatic ductal adenocarcinoma (PDA) is one of deadliest human malignancies with a median survival barely reaching 6 months post-diagnosis. Such epidemiologic data highlight the urgent need to refine current therapies by integrating recent available knowledge on PDA biology. The malignant progression of PDA is characterized by the presence of an exuberant intra-tumoral microenvironment mainly composed of cancer associated fibroblasts (CAFs) and immune cells. This compartment interacts with pancreatic tumor cells surrounded by dense matrix and hypoxic areas, and affects their behavior through a poorly understood network. Indeed, cellular crosstalk between stromal and tumor cells is of major importance in pancreatic ductal adenocarcinoma (PDA). Here, by analyzing the proteomic stromal signature of human PDA, we highlight a possible contribution of the ANXA6/LRP1/TSP1 complex in such crosstalk. Following in vivo validations and stromal localization of each three candidates, we demonstrated that the formation of this complex is restricted to cancer associated fibroblasts (CAFs) cultured under physiopathological conditions (co-culture with macrophages, under hypoxia and lipid deprivation). Increased PDA aggressiveness is dependent on the uptake by tumor cells of CAFs-derived ANXA6+-exosomes. Targeting of ANXA6, and the relevant complex, in CAFs impairs PDA and metastasis occurrence while injection of ANXA6+-exosomes enhances tumorigenesis. Detection of ANXA6+-exosomes in serum is restricted to PDA patients and can distinguish PDA grade. Our data reveal a new CAF-tumor cell crosstalk supported by ANXA6+-exosomes and highlight a therapeutic target and an interesting biomarker for PDA. Citation Format: Julie Leca, Sebastien Martinez, Sophie Lac, Jeremy Nigri, Veronique Secq, Marion Rubis, Nelson Dusetti, Celine Loncle, Julie Roques, Daniel Pietrasz, Stéphane Garcia, Samuel Granjeaud, Mehdi Ouaissi, Jean-Baptiste Bachet, Christine Brun, Juan L. Iovanna, Pascale Zimmermann, Sophie Vasseur, Richard Tomasini.{Authors}. CAF-derived ANXA6+-exosomes support pancreatic cancer aggressiveness and serve as a circulating biomarker. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A61.