Loss of Pten synergizes with c-Met to promote hepatocellular carcinoma development via mTORC2 pathway

Area of Science:

• Oncology
• Molecular Biology
• Hepatology

Background:

• Hepatocellular carcinoma (HCC) is a significant global health challenge with limited therapeutic strategies.
• Aberrant activation of the AKT/mTOR signaling pathway is a common driver in hepatocarcinogenesis.
• The role of mTORC2 in HCC development remains incompletely understood, particularly in vivo.

Purpose of the Study:

• To investigate the functional role of mTORC2 in hepatocellular carcinoma (HCC) development.
• To characterize the interplay between Pten loss, c-Met upregulation, and AKT/mTOR signaling in HCC.
• To establish a novel preclinical model for studying HCC driven by Pten loss and c-Met overexpression.

Main Methods:

• Utilized CRISPR-based gene editing to delete Pten in mouse hepatocytes.
• Employed hydrodynamic injection to overexpress c-Met in conjunction with Pten deletion (sgPten/c-Met model).
• Analyzed molecular signaling pathways (AKT, mTOR) in tumor tissues and employed Rictor conditional knockout mice to assess mTORC2 dependency.

Main Results:

• Concomitant downregulation of Pten and upregulation of c-Met was observed in a subset of human HCC with poor prognosis.
• The sgPten/c-Met mouse model recapitulated HCC development, characterized by increased AKT and mTOR signaling.
• HCC development in the sgPten/c-Met model was critically dependent on an intact mTORC2 complex.

Conclusions:

• mTORC2 plays a crucial role in driving hepatocellular carcinoma (HCC) development, particularly in the context of Pten loss and c-Met activation.
• The sgPten/c-Met mouse model provides a valuable platform for preclinical research and the development of targeted therapies for HCC.
• Targeting mTORC2 may represent a promising therapeutic strategy for specific HCC subtypes.