Overnutrition disrupts metabolic homeostasis to cause obesity and the metabolic syndrome. Epidemiological studies by the Centers for Disease Control and Prevention demonstrate the prevalence of obesity has increased from 30.5% to 42.4% from 1999-2000 through 2017-2018. Obesity and obesity-associated metabolic dysfunction are major risk factors for cancer development and progression in multiple organ sites, including liver, colorectal, pancreatic, and kidney. However, the underlying mechanism by which metabolic dysfunction promotes oncogenesis remains largely unknown.

Obesity and metabolic syndrome frequently result in hepatic steatosis and nonalcoholic steatohepatitis (NASH). NASH has become...

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Overnutrition disrupts metabolic homeostasis to cause obesity and the metabolic syndrome. Epidemiological studies by the Centers for Disease Control and Prevention demonstrate the prevalence of obesity has increased from 30.5% to 42.4% from 1999-2000 through 2017-2018. Obesity and obesity-associated metabolic dysfunction are major risk factors for cancer development and progression in multiple organ sites, including liver, colorectal, pancreatic, and kidney. However, the underlying mechanism by which metabolic dysfunction promotes oncogenesis remains largely unknown.

Obesity and metabolic syndrome frequently result in hepatic steatosis and nonalcoholic steatohepatitis (NASH). NASH has become a leading cause of hepatocellular carcinoma (HCC), the most common type of liver cancer that is especially prevalent in South Texas, the catchment area of UT Health San Antonio’s (UTHSA) NCI-designated Mays Cancer Center.

Working with UTHSA colleagues with class-leading expertise in cancer biology, biochemistry, and structural biology, I will establish a research program dedicated to understanding the molecular mechanism(s) by which metabolic dysfunction promotes NASH and HCC, and to identify molecular targets for developing therapeutic strategies.

To achieve my goals, I will devote my burgeoning independent research career to investigating how overnutrition and obesity promote NASH development and its progression to HCC. Importantly, my recent investigations have discovered an AMPK-caspase-6 axis that senses energy status and plays a pivotal role in NASH development.

We plan to elucidate how deregulation of this novel axis leads to NASH and its progression to HCC. We are confident the proposed studies will not only shed light on the molecular mechanism by which overnutrition and obesity promote tumorigenesis in NASH-associated HCC, but also reveal molecular targets against which novel HCC therapeutics will be developed.

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