The crosstalk between obesity-induced fatty liver and liver metastasis - PROJECT SUMMARY/ABSTRACT CANDIDATE: As a postdoctoral fellow in Dr. Scott Lowe’s lab at MSKCC, my research focuses on the contribution of obesity-induced non-alcoholic fatty liver disease (NAFLD), particularly hepatic lipid accumulation, to liver metastasis from pancreatic ductal adenocarcinoma (PDAC). My long-term goal is to establish an independent research program that aims to dissect the interactions between obesity/NAFLD and metastasis, with the ultimate goal of exploiting this knowledge for therapeutic benefit. The proposed research will form a solid foundation, on which I can establish my own research group by the end of the K99 phase. RESEARCH: Liver is a frequent metastatic site for many cancers including PDAC, and liver metastasis is typically associated with poor prognosis. Obesity-associated NAFLD is the most prevalent chronic liver disease that affects ~25% of the population worldwide, and will become a predominant factor in shaping the niche for metastatic cancers. However, how cancer mechanistically takes advantage of the lipid-rich and inflammatory environment of NAFLD remains largely unknown. My early postdoctoral work show that liver metastasis frequently co-occurs with hepatic lipid accumulation in patients, and fatty acid is a causal driver of PDAC liver metastasis in mouse models of NAFLD. Moreover, in obese mice, the key lipolysis enzyme is unconventionally elevated in hepatocytes adjacent to metastases, which accumulate fatty acid catabolite β-hydroxybutyrate (βOHB) and upregulate Interferon-γ (IFNγ) responses. This proposal will test the hypothesis that metastasis induces lipolysis in neighboring hepatocytes to provide fatty acids, which creates a multifaceted pro-metastatic program. I will leverage functional genetics in mouse models to interrogate lipolysis in the niche hepatocytes (Aim 1), and to determine the contributions of fatty acid-βOHB to epigenome (Aim 2) and IFNγ signaling to the immune niche (Aim 3) in NAFLD-driven metastasis, with spatial analytics to validate these results in human samples. These studies will illuminate the mechanisms that drive liver metastasis in obesity and NAFLD, which could inform new strategies for therapeutic intervention in a growing population of patients. ENVIRONMENT: MSKCC provides an ideal environment for me to accomplish my training and research goals, and successfully transition to an independent faculty position at an academic institution. My mentor Dr. Lowe is a world leader in cancer biology, with expertise on cancer genetics and mouse models. In addition, I have assembled an advisory committee of established scientists with relevant expertise and strong commitment to mentoring (Drs. Farese, Li, and Sherman). Together, all mentors will support my transition to independence by providing valuable research experience and career guidance. With the collaborative environment and broad spectrum of resources at MSKCC, this support network creates optimal conditions for the successful completion of the proposed research and career development plans.
