My research focus is to define the metabolic vulnerabilities that can be exploited to develop an effective therapy for melanoma.
Although I began my independent research program to understand cell death mechanisms in melanoma, our investigations led us to the understanding that metabolic plasticity enable melanoma to resist cell death mechanisms. We are focusing on the following projects with a long-term goal of developing an effective therapy for melanoma.
1. Define the mechanism of ferroxitosis: We reported a novel iron and oxygen dependent cell death called ferroxitosis. Redox cycling agent menadione promotes ferroxitosis in cells cultured under normoxic condition, yet activation of ferroxitosis under hypoxia is contingent upon depletion or inhibition of glycolytic enzyme PKM2. We are investigating the role of nuclear and/or cytosolic functions of PKM2 as well as mitochondrial Complexes in activation of ferroxitosis.
2. Dissect the mechanism of acetate metabolism in melanoma: We reported that acetate metabolism synergizes with glutamine to support melanoma cell survival and tumor growth in a glucose-independent manner. BRAF mutant melanomas rapidly adapt to acetate metabolism in the absence of glucose. Because resistance to BRAF inhibitor therapy involves gain of mitochondrial metabolism, we are currently investigating the mechanism of mitochondrial acetate metabolism.
3. Define the metabolic check points in hematopoietic stem cells: We are closely working with Dr. Broxmeyer to define the metabolic determinants that control hematopoietic stem cell self-renewal and expansion. My goal is to utilize the knowledge gained in melanoma metabolism to promote expansion of hematopoietic stem cell.
