Dissecting the role of invadopodia-mediated degradation in metastasis

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 DESCRIPTION (provided by applicant): Metastasis is the main cause of death in cancer patients. It is the spread of cancer cells from the primary tumor to distant organs and this process requires the ability to degrade the basement membrane and extracellular matrix (ECM). Tumor cells obtain this ability through the formation of membrane protrusions called invadopodia. They are actin-rich subcellular structures that contain a number of regulatory and adaptor proteins in order to recruit proteases, such as metalloproteinases, MMP2 and MMP9, MT1-MMP, to carry out ECM degradation. Our past work demonstrates that invadopodia are essential for tumor metastasis. Given this idea, targeting invadopodia formation in tumor cells is a potential anti-metastasis treatment. Past research on anti-metastasis therapy focused on targeting MMPs because of their direct role in ECM degradation. Although MMP inhibitors demonstrated promising results in preclinical trials, they failed in clinical trials due to broad spectrum of inhibition and toxicity. An alternative to targeting MMPs is to target proteins that ar involved in invadopodia assembly. In this proposal, I aim to better understand invadopodia assembly and how proteases are recruited to invadopodia by performing immunoprecipitation experiments followed by mass spectrometry. In addition, degradation assays, immunocytochemistry, and in vivo studies will be performed to understand the role of the identified protein in invadopodia-mediated metastasis.