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 ß-hydroxybutyrate
(ßOHB) and upregulate Interferon-¿ (IFN¿) 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-ßOHB to epigenome (Aim 2) and IFN¿ 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.