Project 1: Phospholipid Remodeling in Ferroptosis and Cancer

Sloan-Kettering Inst Can Research, New York NY

Investigators

Abstract

Project Summary Ferroptosis, a form of cell death driven by iron-dependent phospholipid (PL) peroxidation, is implicated in various pathological processes, including cancer. As PL peroxidation is a natural consequence of cellular metabolism, surveillance mechanisms functioning to suppress PL peroxidation have been evolved to prevent cells from unwanted ferroptotic death. The overarching goal of this proposal is to investigate novel ferroptosis surveillance mechanisms and to develop mechanism-guided, ferroptosis induction-based cancer therapies, with a focus on PL synthesis and remodeling. We hypothesize that certain specific oncogenic mutations may alter the sensitivity of cancer cells to ferroptosis by modulating ferroptosis surveillance pathways; conversely, ferroptosis can be induced in these cancer cells by exploiting such oncogenic events. In our preliminary study, through a whole genome CRISPR/cas9-activation screen, we identified a novel ferroptosis surveillance pathway independent of canonical surveillance mechanisms mediated by GPX4 (catalyzing the reduction of lipid peroxides) or by enzymes producing lipophilic metabolites with free radical-trapping activity. This novel ferroptosis surveillance pathway is mediated by enzymes involved in PL remodeling and is regulated by signaling events such as estrogen receptor (ER) signaling. Importantly, TCGA analysis reveals that overexpression of a key component of this pathway predicts poor prognosis in liver cancer. Based on these preliminary results, this proposal will determine the precise mechanisms by which PL remodeling regulates ferroptosis and the role of nuclear hormone signaling in modulating PL remodeling and ferroptosis (Aim-1). Relevant to cancer, we will study the role of this novel ferroptosis-suppressing pathway in cancer progression and treatment by focusing on liver cancer (based on TCGA analysis) and breast cancer (ER signaling) (Aim-2). A wealth of interdisciplinary approaches including molecular cellular analysis, cellular and tissue lipidomics and imaging, and mouse models of patient-derived xenograft (PDX), isogenic cell line xenograft, and genetically engineered mouse models (GEMM), will be used. In both aims, there will be significant integration and collaboration with Project 2 and Project 3; and the technical support of the SR Core (Shared Resources Core) will also be used routinely and intensively. Success of the proposed study will lead to an in-depth mechanistic understanding of ferroptosis and its interplay with lipid metabolism, and provide insights into novel, mechanism-based cancer therapies.