p53 loss cooperates with diet to drive liver tumorigenesis

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Presentation Time: 03:15 PM - 04:30 PM
Poster Board Number: B132
Abstract ID: 5860

Presenting Author:
Denada Dibra , Assistant Professor at Univ. of Texas MD Anderson Cancer Ctr.

Abstract:

 

Hepatocellular carcinoma (HCC) has the fastest rising cancer-mortality in the US. Non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and sustained inflammation are frequently associated with obesity and diabetes and are common risk factors for HCC. It is not well-understood how genetic factors co-operate with environmental factors such as diet to induce fatty liver, inflammation, and HCC.  We have developed a spontaneous and somatic mouse model with Trp53 deletion in hepatocytes that develop HCC on a high-fat, choline deficient diet. Transcriptomic analysis of the premalignant stage of the disease revealed that Trp53 loss in hepatocytes of animals fed on this high-fat, choline deficient diet mouse model creates a permissive pre-malignant microenvironment by significantly increasing immune cell infiltration, endogenous retroviruses (ERVs) dysregulation, and fatty liver. Single cell RNA sequencing data revealed that loss of p53 in hepatocytes increased the presence of auto-aggressive CXCR6-expressing NKT cells in the liver. Such changes translate to an increased HCC incidence by 4-fold and shortened time-to-tumor development as compared to mice with a p53 loss alone or diet alone.