Abstract 138: A role for Wnt signaling in regulation of Warburg metabolism in colon cancer

Abstract

Abstract For most aerobic organisms, oxidative phosphorylation (OXPHOS) is the predominant metabolic pathway for production of cellular energy. Compared to anaerobic metabolism, OXPHOS is much more efficient at producing ATP. However, despite an abundance of environmental oxygen and the induction of angiogenesis by a colon cancer tumor, the predominant metabolic pathway utilized is glycolysis. This paradox is also known as Warburg metabolism. In mouse xenograft tumors grown from SW620 colon cancer cells, partial inhibition of beta-catenin dependent Wnt signaling shifts metabolism of the tumor, where glycolysis markers decrease. We also determined that transcription of the pyruvate dehydrogenase kinase-1 gene (PDK1), is regulated by Wnt signaling. PDK1 protein normally inactivates mitochondrial pyruvate dehydrogenase (PDH) through phosphorylation in order to increase the conversion of pyruvate to lactate in the cytosol. We concluded that Wnt signaling directs Warburg metabolism in colon cancer via regulation of a key regulator of glycolysis. When staining for phosphorylated PDH in the xenograft tumors as a measure of active PDK, we discovered a unique spotted pattern of discrete regions of increased phospho-PDH at regular intervals throughout the xenograft tumor. The pattern was accentuated when Wnt signaling was reduced and it was completely abolished with PDK1 expression. This regular spotted pattern was also seen in beta-catenin expression, suggesting that Wnt signaling may be responsible for establishing the spotted pattern. We hypothesized that this patterning could be modeled mathematically as a Turing pattern. Beta-catenin dependent Wnt signaling and its associated inhibitors have been previously characterized to form Turing patterns, or reaction-diffusion systems, in multiple developmental biology systems. Our collaborative group has developed a system of reaction-diffusion equations that describes the formation of these spots in relation to varying concentrations of Wnt signaling, Wnt inhibitors, and nutrients. Included in the model are equations for glycolytic cells, oxidative cells, Wnt signaling activity, Wnt inhibitors, PDK activity, lactate, HIF, and a general nutrient term. Wnt activity and Wnt inhibitor equations are based on the Gierer-Meinhardt activator-inhibitor model. The tumor cells switch metabolic regimes based on PDK activity level (high activity implies a tendency towards glycolysis, and low activity tends toward oxidative phosphorylation). Using novel imaging techniques and mathematical modeling, we have demonstrated that beta-catenin dependent Wnt signaling regulates expression of PDK1 to drive glycolysis in xenograft tumors. This increased glycolysis exists in a regular Turing pattern throughout the tumor. Our mathematical models will allow us to predict changes to tumor metabolism and behavior in response to modulation of Wnt signaling or external stimuli. Citation Format: George T. Chen, Mary Lee, Kira Pate, Kehui Wang, Robert A. Edwards, John S. Lowengrub, Marian L. Waterman. A role for Wnt signaling in regulation of Warburg metabolism in colon cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 138. doi:10.1158/1538-7445.AM2014-138