Abstract 6671: Metabolic predictors in hepatocellular cancer

Background: Obesity and Metabolic dysfunction-associated steatotic liver disease (MASLD) affect nearly a third of the world's population. 20% of MASLD patients progress to Metabolic dysfunction-associated steatohepatitis (MASH). Hepatocellular Cancer (HCC) arises in 4-11% of MASH patients. Recently, we discovered obesity-driven cancers in our mouse models with disruptions to TGF-β signaling (Cell Rep. 2024.43(9):114676 and Sci Transl Med. 2021.13(624): eabk2267). Key metabolic enzymes were evaluated in both mouse models and human cirrhotic patients to elucidate their roles in HCC development. Our Mutant mice exhibited significant sarcopenia, with a notable reduction in muscle mass, mirroring the substantial muscle loss observed in human cirrhotic patients. We identified levels of PKM2, Myostatin and SPTBN1 to be significantly altered in our mouse models of obesity driven HCC. Methods: To investigate the roles of myostatin, SPTBN1, and PKM2 in human HCC progression, serum samples were obtained from 143 patients with cirrhosis and 57 patients diagnosed with HCC. Myostatin and PKM2 serum concentrations were quantified using Somascan proteomic analysis. ELISA was conducted to confirm the observed differences in myostatin and SPTBN1 levels between the cirrhosis and HCC patient cohorts. Additionally, serum samples from 18 cirrhotic patients were longitudinally analyzed over a 5-year follow-up period to monitor their progression to HCC. Results: Elevated myostatin levels were observed in obese mice. Serum myostatin concentrations were significantly higher in patients with HCC than those with cirrhosis (p < 0.05), with a 17% increase in mean levels noted in the HCC cohort. A trend toward increased PKM2 serum concentrations was also observed in HCC patients relative to cirrhosis patients. Somascan proteomic analysis identified elevated myostatin and PKM2 levels in the serum of 18 cirrhosis patients who progressed to HCC over a five-year follow-up period. Validation using ELISA in a prospective cohort (n = 200) confirmed the significant difference in myostatin concentrations between HCC and cirrhosis patients (p < 0.05). Additionally, serum SPTBN1 concentrations were found to be elevated in patients with virus-related cirrhosis and HCC, further supporting its involvement in disease progression. Conclusions: These findings highlight the significant role of Myostatin, PKM2, and SPTBN1 in the progression of cirrhosis to HCC. Elevated myostatin levels in obese mice and HCC patients underscore its potential as a biomarker for disease progression. The observed trend of increased PKM2 concentrations in HCC patients further implicates its role in tumorigenesis, particularly in an immunosuppressive tumor microenvironment. Collectively, these results reinforce the importance of these biomarkers in understanding HCC progression and their potential utility in early detection, risk stratification, and targeted therapeutic strategies. Citation Format: Brandon Mathew, Kazufumi Ohshiro, Krishanu Bhowmick, Xiyan Xiang, Srinivasan Dasarathy, Adrian R. Krainer, Lopa Mishra. Metabolic predictors in hepatocellular cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6671.