p53R245W mutation fuels cancer initiation and metastases in NASH-driven liver tumorigenesis.

Obesity is a significant global health concern. Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are common risk factors for hepatocellular carcinoma and are closely associated with metabolic comorbidities, including obesity and diabetes. The TP53 tumor suppressor is the most frequently mutated gene in liver cancers, with half of these alterations being missense mutations. These mutations produce highly abundant proteins in cancer cells which have both inhibitory effects on WT p53, and gain-of-function activities that contribute to tumor progression. A western diet increases p53 activity in the liver. To elucidate the functional consequences of Trp53 mutations in a NASH-driven liver tumorigenesis model, we generated somatic mouse models with Trp53 deletion or the missense hotspot mutant p53R245W only in hepatocytes and placed mice on a high fat, choline deficient diet. p53R245W in the presence of diet increases fatty liver, compensatory proliferation in the liver parenchyma, and tumor promoting pathways such as KRAS signaling, MYC, and EMT pathways when compared to controls in the premalignant liver. Moreover, p53R245W suppressed transcriptional activity of WT p53 in the liver in vivo under metabolic challenges, and shortened survival and doubling of HCC incidence as compared to control heterozygous mice. Complete loss of Trp53 also significantly accelerated liver tumor incidence and lowered time-to-tumor development compared with WT controls. p53R245W GOF properties increased carcinoma initiation, fueled mixed hepatocholangial carcinoma incidence, and tripled metastatic disease. Collectively, our in vivo studies indicate that p53R245W has stronger tumor promoting activities than Trp53 loss in the context of NASH.