Details

Autor(en) / Beteiligte

• Rajadurai, Charles Vincent

Titel

Molecular Mechanisms of Cancer Cell Invasion During Metastasis

Ort / Verlag

ProQuest Dissertations & Theses

Erscheinungsjahr

2015

Link zum Volltext

• ProQuest

Quelle

ProQuest Dissertations & Theses A&I

Beschreibungen/Notizen

• The Met receptor tyrosine kinase (RTK) and its ligand hepatocyte growth factor (HGF) are potent regulators of epithelial remodeling, dispersal and motility. As such, Met/HGF signaling plays crucial roles in wound healing in the adult and epithelial motility during embryogenesis. In cancer, Met/HGF signaling is often deregulated, and elevated Met activity is associated with increased cancer cell invasion and aggressive tumors with poor patient prognosis. Although the capacity of invasive carcinoma cells to form actin-rich extra cellular matrix (ECM)-remodeling protrusions called invadopodia, has emerged as a major mechanism of cancer cell invasion, prior to this thesis, it was not known whether Met promotes invadopodia formation, and if so, the mechanism. I established that in Met-amplified cancer cells, invadopodia formation is dependent on Met signals and is a key mechanism for cell invasion. Moreover, in invasive carcinoma cells with basal invadopodia forming capacity, ligand, HGF, mediated activation of Met further enhances invadopodia formation. Hence, Met-induced signals may synergize with other oncogenic signals to potentiate cell invasion. Met coordinates invadopodia biogenesis primarily through the scaffold protein Gab1. We identified a novel interaction between Gab1 and cortactin and demonstrated that Gab1-cortactin interaction is essential for Metdependent invadopodia formation. Met co-localizes with cortactin to invadopodia and promotes cortactin phosphorylation, thus driving localized cytoskeletal changes required for invasive membrane protrusion. Signals downstream from multiple RTKs and integrins are coupled to the actin cytoskeleton through, among other mechanisms, changes in membrane phosphatidylinositol composition. In agreement, PI3K, an enzyme whose activity is frequently elevated in cancers, has been identified as a prerequisite for invadopodia biogenesis. I have identified SHIP2, a 5’ inositol phosphatase, as a critical regulator of invadopodia biogenesis. SHIP2 cooperates with PI3K to produce Ptdlns(3,4)P2, a phosphatidylinositol with a key regulatory role in invadopodia assembly. SHIP2 also recruits Mena, a member of the Ena/VASP family of actin elongation factors, which together with its phosphatase activity drive the maturation of nascent membrane protrusions into structures competent for ECM remodeling. I have established a direct interaction between SHIP2 and Met, and provide evidence to support that SHIP2 modulates Met signaling. SHIP2 plays key regulatory roles in clathrin-mediated endocytosis, cell polarity and cell motility, hence providing a rationale to investigate a role for Met-SHIP2 functional interaction in these cellular processes. Collectively, the work from this thesis identifies Met as a potent inducer of invadopodia-mediated ECM remodeling and cell invasion and identifies novel interactions involved in the regulation of the actin cytoskeleton (Gab1-cortactin, SHIP2-Mena and Met/Gab1-SHIP2). As actin cytoskeletal dynamics play a critical role in many vital cellular processes, additional biological functions for these interactions need to be explored.