Grant: Operating Grant

Cancer cells metabolize glucose differently than healthy tissue, a process called the Warburg effect. However, while cancer researchers have made tremendous progress understanding how genetic mutations drive tumor progression, our understanding of the interplay between tumor metabolism and signaling remains poorly defined. At the cell surface, receptor distribution to "membrane domains" regulates receptor signaling. Our labs have worked together to reveal how how two membrane domain regulators, caveolin-1 and galectin-3, function synergistically to promote cancer cell signaling, migration and invasion. We have now found that caveolin-1 promotes the distribution of multiple metabolic enzymes, including pyruvate kinase M2 (PKM2), a key regulator of the Warburg effect, to protrusive cell surface domains called pseudopodia (false feet), that are critical to cancer cell signaling and migration, and thereby metastasis. We will explore the role of caveolin-1 and galectin-3 on the pseudopodial distribution of PKM2 and other metabolic enzymes and how that impacts cellular metabolism. We will then identify the sugar-carrying proteins in pseudopodia that mediate the synergistic activity of galectin-3 and caveolin-1 and determine whether changes in metabolism affect their association with membrane domains. Finally, we will extend these studies to thyroid cancers and determine whether these metabolic changes are also observed in tumors in mice and in human cancers as well as validate whether caveolin-1, galectin-3 and/or PKM2 represent serum markers for improved thyroid cancer diagnosis. The proposed studies, linking membrane domain regulation of pseudopodial signaling to tumor cell metabolism will define novel paradigms for our understanding of cancer progression. It will also lead to the development of serum-based diagnostic assays for clinical assessment of thyroid cancer, impacting directly on management of the treatment of thyroid cancer patients.