title: 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.forename: Julie
authors.initials: J
authors.lastname: Leca
authors.forename: Sébastien
authors.initials: S
authors.lastname: Martinez
authors.forename: Sophie
authors.initials: S
authors.lastname: Lac
authors.forename: Jérémy
authors.initials: J
authors.lastname: Nigri
authors.forename: Véronique
authors.initials: V
authors.lastname: Secq
authors.forename: Marion
authors.initials: M
authors.lastname: Rubis
authors.forename: Christian
authors.initials: C
authors.lastname: Bressy
authors.forename: Arnauld
authors.initials: A
authors.lastname: Sergé
authors.forename: Marie-Noelle
authors.initials: MN
authors.lastname: Lavaut
authors.forename: Nelson
authors.initials: N
authors.lastname: Dusetti
authors.forename: Céline
authors.initials: C
authors.lastname: Loncle
authors.forename: Julie
authors.initials: J
authors.lastname: Roques
authors.forename: Daniel
authors.initials: D
authors.lastname: Pietrasz
authors.forename: Corinne
authors.initials: C
authors.lastname: Bousquet
authors.forename: Stéphane
authors.initials: S
authors.lastname: Garcia
authors.forename: Samuel
authors.initials: S
authors.lastname: Granjeaud
authors.forename: Mehdi
authors.initials: M
authors.lastname: Ouaissi
authors.forename: Jean Baptiste
authors.initials: JB
authors.lastname: Bachet
authors.forename: Christine
authors.initials: C
authors.lastname: Brun
authors.forename: Juan L
authors.initials: JL
authors.lastname: Iovanna
authors.forename: Pascale
authors.initials: P
authors.lastname: Zimmermann
authors.forename: Sophie
authors.initials: S
authors.lastname: Vasseur
authors.forename: Richard
authors.initials: R
authors.lastname: Tomasini
mesh_terms: D000818:Animals; D017317:Annexin A6 / Q000378:metabolism*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism* / Q000473:pathology; D002450:Cell Communication; D055252:Cell-Derived Microparticles / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: D017317:Annexin A6; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D014408:Biomarkers, Tumor; C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D009363:Neoplasm Proteins; C481348:SPZ1 protein, human