The migration of cancer cells away from the primary tumor and their subsequent metastasis to distant organs is the leading cause of mortality in cancer patients. Metastatic cells escape the primary tumor and enter the bloodstream by developing specialized cellular structures called invadopodia that degrade the extracellular matrix (ECM) surrounding the tumor to allow invasion. The assembly of invadopodia is regulated by a family of proteins called Rho GTPases, which play key roles in virtually all stages of cancer progression. In contrast to other cancer associated genes that are frequently mutated in cancer, mutations in Rho genes have been only rarely detected in tumors. In contrast, RhoGEFs and RhoGAPs, two protein families that function upstream of the Rho GTPases to regulate activity, are often misregulated or mutated in cancer. Based on these findings, the development of inhibitors targeting RhoGEFs and RhoGAPs is emerging as a promising approach to cancer therapy, and studies suggest that such inhibitors appear to block many functions associated with tumorigenesis. The objective of this study is to identify novel regulators of invadopodia formation within the RhoGEF and RhoGAP families. This proposal comprises two specific aims:
In Aim 1 we will identify the RhoGEF that activates Rac1, an essential player in invadopodia formation, and in Aim 2, we will screen for RhoGAPs that modulate the formation of invadopodia. For both aims, we plan to characterize the function of the candidates identified during invadopodia formation, cell migration and invasion. It is our expectation that the identified RhoGEFs and RhoGAPs can be used to develop specific inhibitors to slow down or prevent invadopodia formation and thus, invasion and metastasis in different cancer types.
The proposed research seeks to identify and chrachterize novel regulators of invadopodia formation and its contribution to invasive behavior in breast cancer cells, and thus is relevant to the public health problem of metastatic cancer. Thus, the proposed research is relevant to the part of NIH?s mission that pertains to foster fundamental discoveries as a basis for protecting and improving health.
