Metastasis, the process by which tumor cells migrate and invade host tissues away from the primary lesion, is the principal cause of mortality among patients with solid tumors. Expression of the integrin alpha(v)beta3 correlates with tumor progression and metastasis in some of the most aggressive tumors including melanoma, prostate, breast, cervical and pancreatic carcinomas. The overall goal of this proposal is to investigate the signaling pathway by which alpha(v)beta3 mediates metastasis. Recent identification in platelets of a novel selective interaction between the cytoplasmic domain of alpha(v)beta3 and c-src showed that this interaction resulted in subsequent activation of c-src, a kinase whose activity is frequently associated with increased malignancy (8, 9). This model posed a potential mechanism to account for alphav(v)beta3-mediated metastasis. Therefore, we will examine the role of a novel alpha(v)beta3/c-src complex during carcinoma cell migration and invasion. We propose to perform studies aimed at identifying the importance of an alpha(v)beta3 complex for activating c-src in focal adhesions, protein complexes required for cell migration. We will then test whether thiscomplex is required for alpha(v)beta3-mediated cell migration in vitro and determine the significance of of this complex for metastasis in vivo. Results from these experiments have potential translational significance since alpha(v)beta3 is not expressed in many adult cell types, yet it is highly expressed in many invasive tumors and thus represents a potential therapeutic target. These studies seek to identify the most critical elements of alpha(v)beta3 required for it to signal cell migration/invasion and thus may identify the most relevant domain of alpha(v)beta3 to be used for drug targeting. ? ? ?
|Desgrosellier, Jay S; Barnes, Leo A; Shields, David J et al. (2009) An integrin alpha(v)beta(3)-c-Src oncogenic unit promotes anchorage-independence and tumor progression. Nat Med 15:1163-9|