Friday, April 26, 2024
4/26/2024
PROJECT SUMMARY Cancer is a disease of hyperproliferation, and tumor cells increase their metabolic output to support sustained growth, which can lead to increased oxidative stress that damages macromolecules like lipids. Multiple pre- clinical and clinical studies have now demonstrated that dietary antioxidants or common cancer mutations that activate antioxidant pathways can promote tumor growth and metastasis, highlighting the importance of oxidative homeostasis in tumorigenesis. However, whether oxidative stress accumulates to a point of cell death in tumors and the in vivo mechanisms of such oxidative stress-dependent cell death remain elusive. Accumulating evidence indicates that oxidative stress can lead to excessive lipid peroxidation of membrane- associated fatty acids, resulting in membrane rupture and subsequently a non-apoptotic form of cell death, termed ferroptosis. Many intracellular mechanisms have been found to regulate lipid peroxidation and ferroptosis, and there is an emerging body of literature suggesting that cancer cells are highly susceptible to ferroptosis in vitro. In addition, several conventional cancer therapies, such as chemotherapy and radiation, have been shown to effectively eliminate cancer cells by promoting lipid peroxidation and inducing ferroptotic death. However, despite the enthusiasm about ferroptosis and its therapeutic potential in cancer, there are major gaps in our knowledge that will be addressed by this proposal: 1) Does ferroptosis occur in tumors, and is it a barrier to tumorigenesis? 2) Do common cancer mutations regulate oxidative metabolism to suppress ferroptosis? Prior studies have been limited by lack of in vivo tractable models to study ferroptosis, but in this fellowship, we propose a novel preclinical platform to investigate ferroptosis as a bottleneck during tumor progression that can also be exploited therapeutically (Aim1). Building upon these in vivo models, we will also determine how specific cancer mutations rewire metabolic programs to sustain tumor growth and whether overcoming ferroptosis is an underlying mechanism driving disease progression (Aim2).
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
