Novel regulators of cell migration

Abstract

Cell migration is a multistep process which plays a key role during embryonic development, tissue maintenance and immunological surveillance, but drives also disease progression during cancer. A better and detailed understanding of the molecular processes behind cell migration is therefore necessary to develop targeted therapies against metastatic disease. The work presented in this thesis aimed to gain new insights into mechanisms of normal cell motility and cancer cell migration. Furthermore, a negative-feedback mechanism on activated growth factor receptors controlling cell migration was elucidated. As a starting point, an siRNA screen on normal fibroblasts was performed. Previously not described to have a role in cell migration, the phosphoinositide metabolizing enzymes PI3K class III, PIKfyve and MTMR3 were found to be positive hits. Furthermore, a novel function of their product, PtdIns5P, in cell migration was revealed. In a follow-up study with different cancer cell lines, roles in cancer cell migration and invasion were demonstrated. In the second part of the thesis, a novel negative feedback mechanism in FGF signaling involving the MAPK ERK1 and ERK2 was identified, which also has an impact on cell migration. Altered signaling from FGF receptors is known to be involved in carcinogenesis, since they are regulating a range of biological signals, such as proliferation, survival and migration. Understanding the tight regulation of FGF signaling and its complex signaling cascade has also the potential to contribute to the development of more efficient therapies.