Rab GTPases As Drivers of Lipid Droplet Metabolism in Hepatocellular Carcinoma
Developmental Research Program Overview
Hepatic fat accumulation and altered lipid metabolism are known precursors to liver cancer. This proposal is focused on interfering with lipid metabolism in liver cancer cells toward depleting an energy source used during tumor growth and metastasis.
We have identified novel protein targets that are dysregulated in liver cancers and may contribute to early lipid accumulation in liver cells. In this research within the Developmental Research Program of the Mayo Clinic Hepatobiliary SPORE, we are investigating how these proteins control fat accumulation in liver cells and establish their contributions to liver cancer.
Hepatocellular carcinoma (HCC) is the most common type of liver cancer.Therapeutic options are limited, particularly for later-stage cancers. Risk factors for HCC include fatty liver disease, which leads to chronic inflammation and scarring as precursors to HCC. Metabolic rewiring is a hallmark of cancer cells, with altered lipid metabolism proposed to provide a fuel source for the high energetic demands of tumor growth and metastasis, particularly in the nutrient-poor tumor microenvironment.
The goal of this research is to identify critical regulators of lipid storage and metabolism that may support the transition from fatty liver disease to hepatocellular carcinoma and regulate lipid metabolism in liver cancer cells to promote tumor growth, progression and metastasis.
We have identified novel and distinct roles for two related proteins, Rab10 and Rab32, in regulating lipid storage and turnover in hepatocytes and HCC cells. This leads to our overall hypothesis that altered metabolic regulation by the small GTPases Rab10 and Rab32 contributes to liver tumor growth, representing two novel therapeutic targets for disrupting tumor cell metabolism and hepatocellular carcinoma progression. The goal of this proposal is to define the contributions of Rab10 and Rab32 to lipid droplet metabolism and the progression of liver cancer using human hepatocellular carcinoma samples, mouse models of HCC and cultured HCC cells.