Abstract PR04: Germline loss of PK-M2 promotes metabolic syndrome and hepatocellular carcinoma

The pyruvate kinase gene, Pkm , encodes the PK-M1 and PK-M2 isoforms, which are the result of alternative splicing of mutually exclusive exons. While PK-M1 is considered the adult pyruvate kinase isoform, PK-M2 has been closely linked to embryogenesis, tissue regeneration, stem cells, and cancer. Nonetheless, expression of PK-M2 is widespread in wild-type embryonic and adult tissues. To interrogate the functional requirement for PK-M2, we generated and characterized germline PK-M2 null mice ( Pkm2 -/- ). We found that Pkm2 -/- mice are viable and express PK-M1 throughout embryogenesis and into adulthood. Strikingly, PK-M2 loss leads to spontaneous hepatocellular carcinoma (HCC) that is preceded by progressive metabolic disease characterized by insulin resistance, inflammation, and hepatic steatosis. Therefore, in contrast to its role in modulating metabolism to promote cancer in a cell-intrinsic manner, PK-M2 plays a role in maintaining systemic metabolism, thereby preventing metabolic syndrome and HCC. To further dissect the contrasting systemic and cell-intrinsic roles of PK-M2 in the context of cancer, we have combined autochthonous mouse models of cancer from our lab with both the germline null allele of Pkm2 , Pkm2 -/- , and the conditional allele of Pkm2 , Pkm2 fl/fl . This study will allow us to elucidate the distinct cell-intrinsic and cell-extrinsic roles of PK-M2 in both maintaining normal systemic metabolism and aberrant proliferation in the context of cancer. This abstract is also presented as Poster B25. Citation Format: Talya L. Dayton, Vasilena Gocheva, Kathryn M. Miller, William J. Israelsen, Clary B. Clish, Arjun Bhutkar, Shawn M. Davidson, Alba Luengo, Matthew G. Vander Heiden, Tyler E. Jacks. Germline loss of PK-M2 promotes metabolic syndrome and hepatocellular carcinoma. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr PR04.