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| Invited Talk, Saturday, 11:30 – 12:00 |
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| Targeting the cytoskeletal
physics of circulating breast tumor cells to reduce metastasis
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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| Contact:
| Website |
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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. |
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