Clinical Significance of Glycolytic Metabolic Activity in Hepatocellular Carcinoma

SIMPLE SUMMARY: Hepatocellular carcinoma (HCC) is among the most common cancers and causes about 830,000 deaths annually in the world. Metabolic reprogramming is a critical hallmark of HCC, enabling HCC cells to adapt to the high energy demands necessary for fast growth. However, the clinical relevance of metabolic alteration in HCC has not been systematically assessed. By performing cross-species comparison of genomic data from mouse and human tissues, we identified three distinct metabolic subtypes of HCC and uncovered clinical and molecular characteristics associated with three subtypes. Importantly, we showed that the high metabolic subtype is less susceptible to immunotherapy and uncovered a potential mechanism associated with resistance to immunotherapy. ABSTRACT: High metabolic activity is a hallmark of cancers, including hepatocellular carcinoma (HCC). However, the molecular features of HCC with high metabolic activity contributing to clinical outcomes and the therapeutic implications of these characteristics are poorly understood. We aimed to define the features of HCC with high metabolic activity and uncover its association with response to current therapies. By integrating gene expression data from mouse liver tissues and tumor tissues from HCC patients (n = 1038), we uncovered three metabolically distinct HCC subtypes that differ in clinical outcomes and underlying molecular biology. The high metabolic subtype is characterized by poor survival, the strongest stem cell signature, high genomic instability, activation of EPCAM and SALL4, and low potential for benefitting from immunotherapy. Interestingly, immune cell analysis showed that regulatory T cells (Tregs) are highly enriched in high metabolic HCC tumors, suggesting that high metabolic activity of cancer cells may trigger activation or infiltration of Tregs, leading to cancer cells’ evasion of anti-cancer immune cells. In summary, we identified clinically and metabolically distinct subtypes of HCC, potential biomarkers associated with these subtypes, and a potential mechanism of metabolism-mediated immune evasion by HCC cells.