Targeting the Reattachment of Circulating Breast Tumor Stem Cells to Reduce Metastasis

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Stuart Martin photoDr. Stuart Martin

University of Maryland School of Medicine, Baltimore, MD

Breast tumor stem cells that are circulating in the bloodstream can invade distant tissues and lie dormant for long periods of time. Reemergence of these disseminated stem cells as metastatic tumors is a primary cause of patient death. In this webinar, Dr. Stuart Martin from the University of Maryland School of Medicine (Baltimore, MD) discusses his utilization of multiple tools/techniques to discover microtentacles (McTNs) as novel cellular structures that promote the metastatic reattachment of circulating tumor cells in distant tissues. He specifically shows that:

  • Real-time electrical impedance assays with xCELLigence® demonstrate that McTNs influence tumor cell reattachment and migration efficiency, providing a platform for cancer stem cell identification and testing of new antimetastasis therapies
  • Live-cell confocal microscopy reveals that McTNs can penetrate blood vessel walls and also reinforce the multicellular spheres that are formed by many types of cancer stem cells

After training as a Howard Hughes undergraduate research fellow at the University of Virginia, Dr. Stuart Martin received his Ph.D. from the University of California, San Diego. He then completed a Damon Runyon postdoctoral fellowship at Harvard Medical School where he combined functional genomic studies with mouse models of breast tumor metastasis under the mentorship of Dr. Phil Leder. In 2004, Dr. Martin joined the Marlene and Stewart Greenebaum Cancer Center (UMGCC) and the Department of Physiology at the University of Maryland School Of Medicine. He is currently working to apply physical science and engineering approaches to the study of cancer. In order to examine the mechanical properties of circulating tumor cells, Dr. Martin introduced the first optical cell stretcher in the United States. For his innovative research on breast cancer metastasis, in 2010 he was one of only three investigators in the United States recognized with an Era of Hope Scholar Award from the Congressionally-directed Medical Research Program.

REFERENCES:

  1. Matrone, M.A., Whipple, R.A., Thompson, K., Cho, E.H., Vitolo, M.I., Balzer, E.M., Yoon, J.R., Ioffe, O.B., Tuttle, K.C., Tan, M. and Martin, S.S. Metastatic breast tumors express increased tau, which promotes microtentacle formation and the reattachment of detached breast tumor cells. Oncogene. 2010 Jun 3;29(22):3217-27.
  2. Whipple, R.A., Cho, E.H., Balzer, E.M., Matrone, M.A., Vitolo, M.I., Yoon, J.R., Ioffe, O.B., Tuttle, K.C., Yang, J. and Martin, S.S. Epithelial-to-mesenchymal transition promotes tubulin detyrosination and microtentacles that enhance endothelial engagement. Cancer Res. 2010 Oct 15;70(20):8127-37.
  3. Yoon, J.R., Whipple, R.A., Balzer, E.M., Cho, E.H., Matrone, M.A. and Martin, S.S. Local anesthetics inhibit kinesin motility and microtentacle protrusions of human epithelial and breast tumor cells. Breast Cancer Res. Treat. 2011 Oct;129(3):691-701.
  4. Vitolo MI, Boggs AE, Whipple RA, Yoon JR, Thompson K, Matrone MA, Cho EH, Balzer EM, Martin SS. Loss of PTEN induces microtentacles through PI3K-independent activation of cofilin.Oncogene. 2013 Apr 25;32(17):2200-10.
  5. Whipple RA, Vitolo MI, Boggs AE, Charpentier MS, Thompson K, Martin SS.Parthenolide and costunolide reduce microtentacles and tumor cell attachment by selectively targeting detyrosinated tubulin independent from NF-κB inhibitionBreast Cancer Res. 2013; 15(5):R83.
  6. Charpentier MS, Whipple RA, Vitolo MI, Boggs AE, Slovic J, Thompson KN, Bhandary L, Martin SS. Curcumin targets breast cancer stem-like cells with microtentacles that persist in mammospheres and promote reattachment. Cancer Res. 2014 Feb 15;74(4):1250-60.
  7. Perry NA, Vitolo MI, Martin SS, Kontrogianni-Konstantopoulos A. Loss of the obscurin-RhoGEF downregulates RhoA signaling and increases microtentacle formation and attachment of breast epithelial cells. Oncotarget. 2014 Sep 30;5(18):8558-68.
  8. Boggs AE, Vitolo MI, Whipple RA, Charpentier MS, Goloubeva OG, Ioffe OB, Tuttle KC, Slovic J, Lu Y, Mills GB, Martin SS. α-Tubulin acetylation elevated in metastatic and basal-like breast cancer cells promotes microtentacle formation, adhesion, and invasive migration. Cancer Res. 2015 Jan 1;75(1):203-15.
  9. Bhandary L, Whipple RA, Vitolo MI, Charpentier MS, Boggs AE, Chakrabarti KR, Thompson KN, Martin SS. ROCK inhibition promotes microtentacles that enhance reattachment of breast cancer cellsOncotarget. 2015 Mar 20;6(8):6251-66.