Regulation of Wnt Signaling in Invasive Colon Cancer

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 DESCRIPTION (provided by applicant): Colon cancer is the third leading cause of cancer deaths in men and women in the United States. It is defined by the transformation of the colon epithelium from regulated crypt growth to uncontrolled proliferation and invasion into the surrounding mucosa. The primary mutations that drive this transformation target the canonical Wnt signaling pathway by stabilizing ß-catenin to force overexpression of Wnt target genes and Wnt activity. Despite this chronic Wnt activation, the level of signaling activity within the tumoris heterogeneous, with regions of high and low Wnt activity, suggesting environmental signals crosstalk with the pathway. As one in five colon cancer patients are first identified with metastatic disease, and the typical survival for these patients post-diagnosis is five years, there is a pressing need to understand fluctuations in Wnt activity and how the tumor microenvironment can influence colon cancer progression and invasion. This project focuses on how heterogeneity of Wnt signaling in colon cancer is established through its modulation both by autocrine signaling and crosstalk signaling from stromal cells. Our lab and others have recently discovered that decreasing autocrine Wnt signaling in colon cancer cells through inhibition of Wnt ligand secretion leads to increased cell migration and invasion. Based upon published research and my preliminary findings, my overarching hypothesis is that Wnt signaling activity in colon cancer is down regulated during cancer invasion and metastasis. I will address this hypothesis in three specific aims. The first specific aim will identify the Wnt signaling pathway involved in inhibiting mobility. Scratch assays, three-dimensional tumor spheroid assays, and novel microfluidic devices developed here at UC Irvine will be used to measure changes in cancer cell phenotype when various Wnt pathways are perturbed. In the second aim, I will identify the receptors expressed by colon cancer cells that participate in the activation of the pathway. Lastly, I will specifically define the ligand: receptor interaction(s) tat are involved in inhibiting cell migration. Identifying this mechanism has potential therapeutic benefits in understanding how colon cancer metastasizes to distant organs.