Metabolic reprogramming of liver cancer metabolism by the MYC oncogene

Background: Hepatocellular carcinoma (HCC) is among the three leading causes of cancer-related death. HCC is often attributed to multiple etiologies and affects diverse populations worldwide. HCC usually presents with a poor prognosis and six months median survival. Currently, except for early surgical intervention or liver transplantation, no effective cures exist. Despite its significance, a clearer understanding of mechanisms of liver cancer pathogenesis is limited. The temporal relationship between oncogene signaling, in vivo tumor formation and metabolic pathways is poorly understood. The MYC oncogene has proven to be nearly fundamental to tumorigenesis with its activation being amongst the most frequently found alterations in several human cancers, including liver cancer. In HCCs, MYC is associated with poor patient outcome.

Results: Here, we use a switchable model of Myc-driven liver cancer, which we find closely resembles human HCCs at the molecular level, along with hyperpolarized (13)C-pyruvate magnetic resonance spectroscopic imaging (MRSI) to visualize glycolysis in de novo tumor formation and regression. LDHA abundance and activity in tumors is tightly correlated to in vivo pyruvate conversion to lactate and is rapidly inhibited as tumors begin to regress, as are numerous glycolysis pathway genes. Conversion of pyruvate to alanine predominates in precancerous tissues prior to observable morphologic or histological changes. These results demonstrate that metabolic changes precede tumor formation and regression and are directly linked to the activity of a single oncogene. Our study provides evidence for metabolic changes that occur as a consequence of MYC in de novo tumor formation. We propose that these deregulated metabolic pathway components may serve as ideal molecular markers and therapeutic targets to selectively kill liver tumors with elevated MYC expression.