Ether phospholipids metabolism is a latent vulnerability for pancreatic cancer resistance

Abstract

Mitochondria are hubs where bioenergetics, redox homeostasis, and anabolic metabolism pathways integrate through a tightly coordinated flux of metabolites. The essential contributions of mitochondrial metabolism to fuel tumor growth and resistance to therapy are now evident in multiple contexts. However, targeting of mitochondrial metabolism in the clinical setting has repeatedly failed, owing to a narrow therapeutic window and the remarkable ability of tumor cells to activate compensatory metabolic programs. Thus, it is essential to uncover additional mechanisms that may render cancer cells selectively susceptible to treatment and those that enable them to survive when exposed to mitochondrial metabolism-targeted drugs. Here, using pancreatic ductal adenocarcinoma (PDAC) as a disease model, we report that cellular and, in particular, mitochondrial lipid composition affects the sensitivity of cancer cells to pharmacological inhibition of electron transport chain complex I. Metabolomic, including lipidomic, analyses of patient-derived PDAC models uncovered a critical role for monounsaturated fatty acids (MUFAs) and demonstrated that MUFA-linked ether phospholipids have a critical role to sustain homeostasis of mitochondrial reactive oxygen species (ROS). Blocking de novo ether phospholipid biosynthesis in the peroxisomes, sensitized PDAC cells to mitochondrial complex I inhibition by inducing mitochondrial ROS and lipid peroxidation. Biochemical analysis revealed a role of ether phospholipids in the assembly of mitochondrial supercomplexes and ROS production. Together, our data identify an ether phospholipid-dependent mechanism that regulates mitochondrial redox control and contributes to the sensitivity of PDAC cells to complex I inhibition. These findings might lead to novel approaches to target mitochondrial metabolism in cancer cells. Citation Format: Ziheng Chen, I-Lin Ho, Melinda Soeung, Er-Yen Yen, Johnathon Rose, Sanjana Srinivasan, Angela Deem, Sisi Gao, Haoqiang Ying, Giulio Draetta. Ether phospholipids metabolism is a latent vulnerability for pancreatic cancer resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1683.