Centre de Recherche en Cancérologie de Toulouse (CRCT)-UMR 1037
contact : Christel Larbouret (Inserm-IRCM)
The fibroblastic stroma comprises most of pancreatic adenocarcinoma mass and is remarkably devoid of functional blood vessels leaving an unresolved question of how pancreatic cancer cells obtain their essential metabolites and especially water-insoluble lipids. Contrary to the previously held assumption that cancer cells uptake lipids directly from the interstitial fluid, we have found a critical role for cancer-associated fibroblasts (CAFs) to obtain and transfer blood-borne lipid particles to cancer cells via trogocytosis, a process of “nibbling” of plasma membranes between two cells engaged in synapse-like membrane contacts. Whereas trogocytosis has been described in normal development, the biochemical and signaling regulators of trogocytosis between CAFs and PDAC cells have not been defined. We determined that CAF membrane trogocytosis is triggered by externalized phosphatidylserine (PtdSer), and blockade of PtdSer in vitro transiently deters trogocytic uptake of CAF membranes. We have also discovered a phospholipid scramblase anoctamin 6 (ANO6) expressed in CAFs as the essential trogocytosis regulator to promote cancer cell survival. Mechanistically, CAF-cancer cell membrane contacts induce cytosolic calcium influx via Orai channels, which activates ANO6 and results in phosphatidylserine exposure on CAFs. As a promising therapy target, ANO6 protein is highly expressed in PDAC tumor mass in cancer cells, endothelial cells and CAFs and is a negative prognostic biomarker for survival. Depletion of ANO6 in co-implanted CAFs dramatically reduced the growth of orthotopic pancreatic tumor grafts. Furthermore, pharmacologic inhibitors of ANO6 with clinically available antibiotics niclosamide or clofazimine potently blocked cholesterol uptake in vivo by PDAC cells.