Role of c-Myc-PP2A negative feedback control in liver biology: new avenues for improved treatment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a deadly cancer with limited treatment options. This project exploits our recent discovery of spontaneous HCC development in mice lacking the B'65 subunit of PP2A, a phosphatase family with tumor suppressive functions. The observed HCC phenotype was causally linked to loss of a negative feedback loop between the oncoprotein c-Myc and PP2A, which, due to PP2A inactivity, results in full-blown c-Myc oncogenicity. The current projects aims at translating this knowledge into improved therapies for HCCs. Our main goals are: (1) to characterize the molecular mechanisms of the c-Myc-PP2A feedback loop in normal human hepatocytes and mouse liver, (2) to determine how loss of this feedback control affects liver regeneration, human hepatocyte transformation, and spontaneous and carcinogen-induced HCC development in mice, (3) to identify and characterize concurrent alterations of PP2A and MYC in human HCC, and to assess the predictive marker potential of PP2A dysfunction for multi-kinase inhibitor therapies in HCC, and (4) to exploit this fundamental information to provide proof-of-concept for a novel therapeutic strategy for HCC treatment. The project will advance conceptual insights in normal liver biology and HCC pathogenesis, and holds the potential to improve HCC treatment.