Stuart S. Martin
 

Greenebaum NCI Cancer Center, University of Maryland School of Medicine, 655 W. Baltimore Street, Baltimore MD 21201, USA

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Circulating tumor cells (CTCs) are an emerging indicator of metastatic tumor recurrence and a potential therapeutic target.  However, the great majority of current drug development for metastasis focuses on the invasion and motility of tumor cells attached to extracellular matrix.  Comparatively little is known about therapeutic targets in CTCs or the effects of existing chemotherapies on CTCs.  Our lab has recently discovered that detached and circulating breast tumor cells generate dynamic membrane microtentacles (McTNs), that promote CTC aggregation and reattachment.  These McTNs arise due to imbalances in the physical forces of microtubule extension and actin cortical contraction, specifically in detached epithelial cells.  We have identified numerous molecular alterations that promote McTNs by altering this physical force balance, including epithelial-to-mesenchymal transition (EMT) and activation of the Src tyrosine kinase.  The cytoskeletal mechanism supporting McTNs matches the mechanism by which CTCs bind to blood vessel walls in vivo.  Since large epithelial tumor cells are crushed when pushed through narrow capillaries by blood flow, we are targeting McTNs to reduce tumor cell reattachment and increase the fragmentation of CTCs.  In addition, we have recently reported that the common tubulin-stabilizing drug, Paclitaxel, enhances McTNs and tumor cell reattachment. Surgery and neoadjuvant chemotherapy can increase CTCs up to 1000-fold, emphasizing that a better understanding of the physical forces in the CTC cytoskeleton is required to avoid inadvertently increasing metastatic risk while targeting cell division.