Abstract 1571: Cancer associated fibroblasts sustain critical dependency of pancreatic cancer cells on exogenous lipids
Authors: Ogier Charline , Klochkova Alena , Bayarmagnai Battuya , Gabitova Linara , Restifo Diana , Surumbayeva Aizhan , Franco-Barraza Janusz , Costa Debora Vendramini , Francescone Ralph , Gardiner Jaye , Nicolas Emmanuelle , Handorf Elizabeth A. , Cai Kathy Q. , Cukierman Edna , Astsaturov Igor 
Published: June 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) cells derive their resistance to therapy and aggressive clinical course from the symbiotic signaling and metabolic interactions with cancer-associated fibroblasts (CAFs). CAFs have been shown to provide nutrients to "parasitic" PDAC cells including water soluble glucose and amino acids. In hypoxic tumor microenvironments, aggressive PDAC are functional auxotroph for lipids, and scavenge exogenous lipids to build cellular membranes. However, the mechanism by which PDAC cells obtain these water-insoluble essential membrane building materials remains poorly understood. To gain insights into the mechanism of lipid scavenging, we generated cholesterol-auxotrophic human and mouse PDAC PDAC cells since cholesterol is the major constituent of lipid cellular membranes. Here, we discovered that PDAC cells utilize CAFs as a main source of lipids in vivo through direct heterotypic cellular contacts. In this process, PDAC cells directly acquire the CAF plasma membrane (PM) via trogocytosis. In response to yet unidentified paracrine “feed me” signals activating CAF-dependent trogocytosis, CAFs upregulate phosphatidylserine (PtdSer) on the outer leaflet of the PM. Consequently, blockade of PtdSer on CAFs partially deterred trogocytic transfer of CAF membranes to PDAC cells in vitro. Furthermore, Ca2+-dependent phospholipid scramblase TMEM16F is a critical regulator of PtdSer externalization. TMEM16F is highly expressed in human PDAC CAFs compared to fibroblasts isolated from the matching adjacent non-malignant pancreatic tissues CAFs deficient in TMEM16F scramblase exhibited markedly reduced ability to support the growth of cholesterol-auxotrophic PDAC cells cultured in lipid depleted media. We propose trogocytosis as a new mode of lipid scavenging by PDAC cells from CAFs involving activation of Ca2+-dependent phospholipid scramblase TMEM16F in CAFs and increased expression of PtdSer as “eat me” signals on CAF PM. To inactivate trogocytosis, we nominate TMEM16F as a plausible PDAC therapy target using clinically available TMEM16 inhibitors with a potential for impact on treatment of PDAC patients in the near term.
Citation Format: Charline Ogier, Alena Klochkova, Battuya Bayarmagnai, Linara Gabitova, Diana Restifo, Aizhan Surumbayeva, Janusz Franco-Barraza, Debora Vendramini Costa, Ralph Francescone, Jaye Gardiner, Emmanuelle Nicolas, Elizabeth A. Handorf, Kathy Q. Cai, Edna Cukierman, Igor Astsaturov. Cancer associated fibroblasts sustain critical dependency of pancreatic cancer cells on exogenous lipids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1571.