Tumors contain multiple subpopulations of cells some of which may contribute to therapeutic resistance. Moreover phenotypic states in cancer (stem-like; invasive; proliferative; and differentiated) are dynamic and reversible, yet use many of the same signaling pathways implicated in activation and self-renewal of physiological stem cells. Of these, the Wnt/b-catenin signaling pathway plays a major role in stem cell activation and differentiation, and is frequently constitutively activated in cancers. My preliminary results indicate that surprisingly, oleic acid can substitute for Wnt in activation of b-catenin signaling. Adipocytes can play a key role in stem cell activation, can transfer lipids to cancer cells, and are frequently encountered during cancer cell invasion. I hypothesize that lipid uptake by cancer cells will alter metabolism and drive phenotype-switching via b-catenin signaling. This project therefore aims to investigate the biological and metabolic consequences of lipid uptake by cancer cells and will use melanoma as a model system since the key regulators of phenotype-switching in this cancer are known to be targeted by b-catenin signaling. Specifically, I will use standard cell biology techniques to identify the repertoire of lipids able to trigger nuclear localization of b-catenin and the biological consequences of lipid uptake (invasiveness; proliferation; differentiation etc); integrative genomics (ChIP-seq and RNA-seq) to identify direct b-catenin target genes and their relationship to those targeted by the master regulator of the melanocyte lineage, MITF, that is known to interact directly with b-catenin; and metabolomics to identify how lipid uptake and de-regulation of b-catenin signaling affect cellular metabolism. The results will provide a key insight into how lipid signalling can impact on cancer biology and potentially activate physiological stem cells, as well as provide high-level training in emerging technologies.
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