Cooperation Between Distinct Cancer Driver Genes Underlies Intertumor Heterogeneity in Hepatocellular Carcinoma

Area of Science:

• Oncology
• Genetics
• Translational Research

Background:

• Hepatocellular carcinoma (HCC) exhibits significant genetic diversity, limiting current therapy effectiveness.
• Existing mouse models fail to fully represent HCC's inter-tumor heterogeneity.
• Understanding this diversity is crucial for developing personalized HCC treatments.

Purpose of the Study:

• To create a novel collection of HCC mouse models reflecting human HCC diversity.
• To investigate the impact of combined genetic alterations on HCC development.
• To establish models for mechanistic and translational studies.

Main Methods:

• Hydrodynamic tail-vein injections were used to introduce genetic alterations in mouse models.
• Combinations of established HCC oncogenes (MYC, β-catenin) with other frequently mutated HCC genes were tested.
• Generated HCC mouse models and cell lines were characterized histopathologically, immunologically, and transcriptomically.

Main Results:

• Nine out of 23 tested genetic alteration pairs successfully induced HCC.
• The resulting HCCs displayed diverse histopathology, immune microenvironments, and transcriptomes.
• MYC expression levels modulated β-catenin activity, highlighting expression-dependent phenotypes in tumor heterogeneity.

Conclusions:

• A novel collection of murine HCC models and cell lines was established.
• These models demonstrate the role of driver genes in various contexts.
• The models facilitate mechanistic and translational research for HCC.