Wnt signaling directs a metabolic program of glycolysis and angiogenesis in colon cancer

• Published in: The EMBO journal 2014-07, Vol.33 (13), p.1454-1473
• Main Authors: Pate, Kira T, Stringari, Chiara, Sprowl-Tanio, Stephanie, Wang, Kehui, TeSlaa, Tara, Hoverter, Nate P, McQuade, Miriam M, Garner, Chad, Digman, Michelle A, Teitell, Michael A, Edwards, Robert A, Gratton, Enrico, Waterman, Marian L
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Cell Line, Tumor; colon cancer; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colorectal cancer; EMBO03; EMBO21; EMBO24; fluorescence lifetime imaging; Glucose - genetics; Glucose - metabolism; Glycolysis; Humans; Kinases; Metabolism; Mice; Mitochondria - genetics; Mitochondria - metabolism; Mitochondria - pathology; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Oxygen Consumption - genetics; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Tumor Microenvironment; Tumors; Wnt; Wnt Signaling Pathway
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.201488598

Much of the mechanism by which Wnt signaling drives proliferation during oncogenesis is attributed to its regulation of the cell cycle. Here, we show how Wnt/β‐catenin signaling directs another hallmark of tumorigenesis, namely Warburg metabolism. Using biochemical assays and fluorescence lifetime imaging microscopy (FLIM) to probe metabolism in vitro and in living tumors, we observe that interference with Wnt signaling in colon cancer cells reduces glycolytic metabolism and results in small, poorly perfused tumors. We identify pyruvate dehydrogenase kinase 1 (PDK1) as an important direct target within a larger gene program for metabolism. PDK1 inhibits pyruvate flux to mitochondrial respiration and a rescue of its expression in Wnt‐inhibited cancer cells rescues glycolysis as well as vessel growth in the tumor microenvironment. Thus, we identify an important mechanism by which Wnt‐driven Warburg metabolism directs the use of glucose for cancer cell proliferation and links it to vessel delivery of oxygen and nutrients. Synopsis Waterman and colleagues functionally characterize PDK1 as crucial contributor toward Wnt‐dependent metabolic and angiogenic transformations during colon cancer progression. Discover oncogenic Wnt signaling as driver of glycolytic metabolism and angiogenesis. Identify PDK1 as direct, executing Wnt target. Develop in vivo FLIM to image metabolic adaptations in living, perfused tumors. Graphical Abstract Waterman and colleagues functionally characterize PDK1 as crucial contributor toward Wnt‐dependent metabolic and angiogenic transformations during colon cancer progression.