Targeting microtubule stabilization to reduce breast tumor metastasis

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DESCRIPTION (provided by applicant): Cytoskeletal alterations are known to influence the metastatic success of circulating tumor cells (CTCs). However, studies of the tumor cell cytoskeleton are almost exclusively focused on cells attached to surfaces or extracellular matrix leaving a significant knowledge gap relevant to metastasis. Recent work from the PI's research group has demonstrated that the cytoskeleton of detached and circulating tumor cells responds very differently from cells attached to extracellular matrix. Specifically, detached tumor cells produce unique tubulinbased microtentacles (McTNs) that promote the reattachment of CTCs to endothelial cell layers. Imaging in live animals has demonstrated that CTCs reattach to blood vessel walls via a cytoskeletal mechanism that matches McTNs. Importantly, since McTNs are supported by tubulin, the common breast cancer drug, Paclitaxel (Taxol), actually strengthens McTNs and speeds tumor cell reattachment. Developing cancer drugs aimed at inhibiting attached tumor cell motility by targeting the actin cytoskeleton also enhance McTNs. These results emphasize the importance of determining whether cancer drugs aimed at cell division or the motility of attached tumor cells could have inadvertent effects that would actually increase metastatic risk. Since both surgery and neoadjuvant chemotherapy can strongly increase the levels of CTCs, it is important to understand which molecular targets will reduce the metastatic efficiency of CTCs and which may increase metastatic risk. Nearly 90% of human solid tumors arise as carcinomas from epithelial cells, whose large size and rigidity often lead to their fragmentation in narrow capillaries. This restraint on metastatic efficiency could impose a selective pressure for circulating carcinoma cells to develop mechanisms to reattach to blood vessel walls and escape fragmentation. Recent work in the PI's lab has identified that McTNs are increased when microtubules are stabilized via either genetic alterations or chemical treatments. This study will test the hypothesis that microtentacles arise from specific reinforcements of microtubules that can be targeted therapeutically to reduce breast tumor metastasis. Predictions of this hypothesis will be tested in the following specific aims: 1) Define the role of tubulin detyrosination during McTN generation and metastasis. 2) Target expression of the microtubule-binding protein, Tau, to reduce McTNs. 3) Use orthotopic mouse model and patient-derived CTCs to gauge paclitaxel effects on McTNs. The long-term goals of this project are to define the molecular mechanisms that govern microtubule stabilization in circulating tumor cells. Extending our understanding of McTN structure and molecular regulation as well as examining McTN incidence and function in CTCs derived from human breast cancer patients will both identify novel therapeutic targets and reveal potential metastatic risks of current cance drugs.