Impact of Cytoskeletal Regulators on Cancer Cell Stromal Invasion

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Cancer cell invasion of stromal tissues requires a complex interplay between major components of the cytoskeleton. This interplay is governed by cytoskeletal regulators, which endow cancer cells with the ability to dynamically alter their structure in order to invade through stromal tissue when metastasizing. To determine critical modulators of invasion, I was part of a collaborative team that employed RNAi screening to identify pathways required for cancer cell attachment to, and invasion though, endothelia. Two cytoskeletal regulators emerged as top hits from the screen: keratin-associated protein 5-5 (Krtap5-5) and the MST3 kinase. The first part of my dissertation (Aim 1) involved characterizing Krtap5-5, a regulator of keratin intermediate filaments that had no previous reported role in cancer, yet I have determined that it is rate-limiting for the vascular invasive phenotype of cancer cells. The remainder of my dissertation (Aim 2) is now focused on MST3, an actin cytoskeleton regulator that is one of the five known mammalian MST homologues of the Drosophila Hippo kinase. This research proposal will first explore whether the MST3 kinase is required for stromal invasion by triple-negative breast cancer cell lines, with the hypothesis that MST3 may represent a unique cytoskeletal vulnerability for this often aggressive and therapeutically resistant disease. MST3's role in stromal invasion will be assessed in a series of models often used to predict metastatic spread, one of which is a cutting-edge microfluidic device. Potential crosstalk between MST3 and the Hippo signaling pathway will also be studied by focusing on important signaling nodes of the actin cytoskeleton, namely Rho and Rac. Upon completion, my dissertation will produce distinct insights into the impact of cytoskeletal regulators on cancer cell invasion of the stroma. After graduating, I seek to expand my research experience in tumor-stromal crosstalk to include cells of the immune system (Aim 3) and plan to continue my education as a postdoctoral researcher.