The general goal of this renewal proposal is to understand the biomechanical mechanism by whichextracellular matrix (ECM) regulates angiogenesis during tumor development, with a specific focus on howphysical interactions between capillary endothelial (CE) cells and their ECM adhesions control directional cellmotility. During the last grant period, we showed that mechanical changes at the cell-ECM interface governthe direction in which cells move because local variations of physical force distributions dictate where cellswill form focal adhesions (FAs) and extend new motile processes when stimulated with soluble motilityfactors. Analysis of this motility steering mechanism and the mechanism of FA repositioning revealed acentral role for transfer of mechanical forces across transmembrane integrin receptors which elicit signalingresponses that, in turn, activate additional p1 integrin receptors. Other signaling molecules, including thesmall GTPases, Rho and Rac, also contribute to the mechanism by which ECM influences FA location, andcells that lack the FA protein paxillin fail to exhibit spatial coupling between FA formation and lamellipodiaextension. In separate studies, we discovered that an upstream regulator of Rho, p190RhoGAP, may linkcytoskeletal signaling to cell motility and angiogenesis by another mechanism: this Rho inhibitor regulatesthe activity of the transcription factor TFII-I and thereby controls expression of the vascular endothelialgrowth factor (VEGF) receptor VEGFR2. Thus, the specific aims include: 1) To explore how stress-dependent activation of (31 integrin and Rho alter focal adhesion position, 2) To determine how focaladhesions govern lamellipodia positioning and directional cell migration, and 3) To analyze how cytoskeletalsignaling through p190RhoGAP influences VEGFR2 gene expression. These studies will include in vitromechanistic experiments as well as in vivo studies in a tumor angiogenesis model to determine the potentialclinical relevance of our findings. Understanding the molecular basis of this mechanical signaling response that controls direction migrationof capillary blood vessel cells could lead to identification of new molecular targets for therapeutic interventionin virtually all solid cancers that require continuous angiogenesis for their own growth and expansion.
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