Hepatocellular carcinoma (HCC) is highly metastatic and represents a major cause of cancer deaths in the United States. The predominantly Hispanic population of our South Texas catchment area experiences high HCC and mortality rates due to the prevalence of obesity and nonalcoholic steatohepatitis (NASH). The metabolic stress induced by these pathological conditions causes chronic inflammation that represents a key factor in the development of HCC.

How metabolic stress and inflammation help create a pro-tumorigenic environment in the liver remains to be delineated. Clinical trials targeting macrophages yield notable clinical benefits in tackling HCC. However, given the essential roles of mac...

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Hepatocellular carcinoma (HCC) is highly metastatic and represents a major cause of cancer deaths in the United States. The predominantly Hispanic population of our South Texas catchment area experiences high HCC and mortality rates due to the prevalence of obesity and nonalcoholic steatohepatitis (NASH). The metabolic stress induced by these pathological conditions causes chronic inflammation that represents a key factor in the development of HCC.

How metabolic stress and inflammation help create a pro-tumorigenic environment in the liver remains to be delineated. Clinical trials targeting macrophages yield notable clinical benefits in tackling HCC. However, given the essential roles of macrophages in tissue homeostasis, unselective elimination of general macrophage populations leads to severe side effects. Therefore, new treatment regimens that specifically prevent the accumulation of macrophages within the liver tumor microenvironment will circumvent the shortcomings of current HCC therapeutics. In this regard, our recent work reveals that metabolic stress promotes lipid peroxidation to generate a massive amount of pathogenic oxidized phospholipids (OxPLs) that become concentrated in pre-tumor niches to recruit macrophages and accelerate the initiation of NASH-associated HCC. Importantly, neutralization of OxPLs with a single-chain antibody leads to the arrest of NASH and prevents its progression to HCC.

Capitalizing on our mechanistic findings and unique mouse models, we will:

1. Interrogate whether targeting OxPLs after HCC onset would prevent HCC progression and metastasis
2. Elucidate the role of a novel signaling axis in OxPL-induced NASH and HCC development.

These endeavors will constitute the core of our research program at UT Health San Antonio, and they will exert broader impact in understanding the etiology and devising treatment strategies for other tumor types that are marked by metabolic stress and chronic inflammation.

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