CHEMOTACTIC SIGNALS REGULATING HUMAN NEUTROPHIL AND BREAST METASTATIC MIGRATION

Division Of Basic Sciences - Nci

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Abstract

We are interested in assessing whether mammalian cells have retained the signaling pathways and migration behavior that Dictyostelium use when they relay chemotactic signals during chemotaxis. Our work focuses on two aspects of neutrophil chemotaxis. First, we set out to determine the mechanism by which chemoattractants increase cAMP production. In Dictyostelium, ACA activation requires inputs from heterotrimeric G proteins, phosphoinositide-3 kinase (PI3K), and the target of rapamycin complex 2 (TORC2). A second project is aimed at understanding the role of signal relay during neutrophil chemotaxis. Chemokines have also been implicated in the progression of cancer, particularly during breast cancer metastasis. Moreover, a shift from mesenchymal (collective) to amoeboid movement is observed during metastasis. As cancer cells transition from clusters to single, amoeboid-like cells, they often migrate in a head-to-tail fashion and form files of cells that move along paths of least resistance. Metastatic cancer cells therefore revert to a very primitive and efficient mode of migration shared by hematopoietic and Dictyostelium cells. We hypothesize that the invasive potential of breast cancer cells is related to their ability to upregulate their chemotactic machinery, and is coupled to a dedifferentiation program that leads to primitive chemotactic behaviors such as amoeboid-like single cell migration and sheet/group migration.