ANO6-mediated trogocytosis of cancer-associated fibroblasts promotes pancreatic cancer cell growth and immune suppression

In pancreatic ductal adenocarcinoma (PDAC), the fibroblastic stroma constitutes most of the tumor mass and is remarkably devoid of functional blood vessels, leaving unresolved how PDAC cells obtain essential metabolites and water-insoluble lipids. We find that cancer-associated fibroblasts (CAFs) acquire and transfer lipids from blood-borne particles to PDAC cells through trogocytosis of CAF plasma membranes, a process requiring the CAF-expressed phospholipid scramblase anoctamin 6 (ANO6) to promote PDAC cell survival. Cancer cells and CAFs form synapse-like contacts that induce cytosolic calcium influx in CAFs through Orai channels, activating ANO6 and driving phosphatidylserine exposure on CAF membranes, which initiates trogocytosis and transfer of membrane lipids, including cholesterol, to PDAC cells. This ANO6-dependent phosphatidylserine externalization also supports CAF-mediated immunosuppression of cytotoxic T cells through trogocytosis. Blockade of ANO6 antagonizes tumor growth, partly by disrupting cholesterol delivery to cancer cells, and attenuates immune suppression, identifying ANO6 as a candidate therapeutic target in PDAC. Ogier et al. uncover that cancer-associated fibroblasts fuel pancreatic tumor growth and immune suppression by transferring membrane lipids to cancer cells through anoctamin 6-dependent trogocytosis.