Metastatic tumor cells are distinguished by their ability to invade the basement membrane of epithelialbarriers and migrate to distant sites. Recent studies from this program demonstrate that host macrophagesare critical for the motility and invasion of tumor cells, due to a paracrine loop involving the mutual signalingand chemotaxis between macrophages and tumor cells. PI3K is a critical regulator of cell motility, anddistinct PI3K isoforms are required for regulation of actin-based motility in tumor cells versus macrophages.We propose to use isoform-specific inhibitors of Class IA PISKs as well as genetic approaches to examinethe requirement for PI3K-mediated motility of both tumor cells and macrophages during invasion andmetastasis. By selectively inhibiting the motility of tumor cells versus macrophages, we will test whether theenhanced tumor cell chemotaxis observed in the presence of macrophages requires pre-exposure tomacrophage-derived cytokines, versus the presence of continuous macrophage signaling during coordinatedmigration of the two cell types. We will also examine the metastatic behavior of tumor cells expressingactivating mutations of PI3K that are commonly found in human breast cancer. The unique assaysdeveloped by this program will allow a detailed analysis of how oncogenic p110ct mutants affect the tumorcell-macrophage paracrine loop. Finally, studies from this program have shown that genes coding forproteins that modulate the myosin-ll regulatory pathway are up-regulated in invasive tumor cells and that theamoeboid motility of tumor cells in a 3D matrix is mediated by the myosin-ll regulatory pathway. Given thesefindings, and our observations that PI3K regulates myosin-ll-based contractility in tumor cells, we willexamine the PI3K isoform-dependence of myosin-ll phosphorylation, the identification of intermediarysignaling pathways in tumor cells and macrophages, and the subsequent effects on motility and invasion.These studies will complete our analysis of the motility cycle as it relates to the invasion signature, and leadto new insights into the role of macrophage-tumor cell paracrine signaling during metastasis.
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