Low adipocyte hepatocellular carcinoma is associated with aggressive cancer biology and with worse survival.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide, and non-alcoholic fatty liver disease is strongly associated with its development. To explore the role of adipocytes in HCC, we investigated intratumoral adipocytes, also known as cancer-associated adipocytes (CAA). Based on our prior breast cancer findings, we hypothesized that low intratumoral adipocytes would be associated with aggressive cancer biology, worse tumor microenvironment (TME), and clinical outcomes. The Cancer Genome Atlas (TCGA) was used and validated by the Gene Expression Omnibus (GEO) cohort. xCell algorithm was used to quantify intratumoral adipocytes and top 90% were defined as adipocyte high (AH) and bottom 10% as adipocyte low (AL). We found that AL-HCC was significantly associated with worse disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS). AL-HCC were higher-grade, had high MKI67 expression, enriched cell proliferation-related gene sets, and had increased altered fraction, aneuploidy, and homologous recombination defects. Also, anti-cancer immune cells, CD8, Th1, and M1 cells, as well as pro-cancer Th2 cells were increased in AL-HCC. Micro-RNAs miR-122 (associated with cholesterol metabolism) and miR-885 (associated with liver pathologies) were significantly increased in the AL TME. In conclusion, we found that AL-HCC has worse patient outcomes and is biologically more aggressive with enhanced cell proliferation. Our findings take initial steps to clarify the role of adipocytes in HCC. AJCR