Abstract B42: Metabolic changes, associated with loss of the tumor suppressor LKB1, promote tumorigenesis

Abstract

Abstract The LKB1 tumor suppressor encodes a serine/threonine kinase that serves as a master regulator of energy metabolism. Germline mutations in LKB1 cause the Peutz-Jeghers polyposis and cancer syndrome and are associated with a high risk of pancreatic cancer development. Despite being the subject of extensive investigation for more than 15 years, the primary mechanisms of LKB1-mediated tumor suppression remain poorly defined. The best-characterized function of LKB1 in cell physiology is to coordinate adaptation to a drop in ATP stores, shutting down multiple biosynthetic processes and favoring catabolic pathways, thereby restoring cellular energy charge. Since LKB1 has pleiotropic effects on cell polarity, migration, and inflammation in addition to cell metabolism, it remains uncertain to what extent LKB1-mediated tumor suppression involves its roles in metabolic reprogramming. In this regard, LKB1 inactivation renders cells vulnerable to a number of metabolic stress stimuli such as glucose deprivation or reactive oxygen species (ROS), indicating that alterations in metabolic control may decrease, rather than increase, the fitness of LKB1 deficient cells. To resolve these questions, we have conducted comprehensive metabolic profiling and functional studies that revealed that LKB1 inactivation results in greatly improved efficiency of nutrient acquisition and utilization, which fuels accelerated cell growth and tumorigenesis. By using a series of primary epithelial culture systems and genetically engineered mouse models coupled with integrative metabolic profiling and flux analyses, we find that LKB1 loss potentiates glucose uptake and glycolysis, and diverts a significant amount of glycolytic intermediates toward biosynthetic processes. Most notably fatty acid and nucleotide pools are greatly expanded upon LKB1 inactivation. This extensive metabolic reprogramming results in a shift in the nutrient requirements of LKB1 mutant cells including a reduced dependence on select exogenous amino acids and greatly increased need for glutamine and glucose. Collectively, our studies uncover adaptive metabolic changes conferred by LKB1 inactivation and suggest potential targetable vulnerabilities of LKB1 mutant cancers. Citation Format: Filippos Kottakis, Brandon N. Nicolay, Nagle M. Julia, Marc Liesa, Orian S. Sirihai, Nicholas J. Dyson, Nabeel Bardeesy. Metabolic changes, associated with loss of the tumor suppressor LKB1, promote tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B42.