655 W. Baltimore Street BRB 10-027
Education and Training
I received my Ph.D. from the University of California-San Diego in Biomedical Sciences, a program that combined molecular cell biology with pharmacology and physiology. As a graduate student with Dr. Jerry Olefsky, I focused on insulin-stimulated rearrangement of the actin cytoskeleton, and demonstrated that PI3-Kinase was sufficient to induce actin membrane ruffling and stress fiber breakdown. After graduating in 1998, I moved to Dr. Phil Leder's lab at Harvard Medical School to study how cell shape and the actin cytoskeleton can influence cell survival. My postdoctoral training allowed me to combine functional genomic tissue culture systems with mouse models of breast cancer. In 2004, I joined the Department of Physiology at the University of Maryland School of Medicine as an Assistant Professor. I am currently a Professor in the Departments of Pharmacology and Physiology. I also serve as co-leader of Hormone-Related Cancers (HRC), a group of 45 investigator labs that are focused on breast, prostate and ovarian cancers within the Marlene and Stewart Greenebaum Comprehensive Cancer Center. In 2020, I was honored to be awarded the Drs. Angela and Harry Brodie Endowed Professorship in Translational Cancer Research.
Lee RM, Vitolo, MI, Losert, W, Martin SS. (2021). Distinct roles of tumor associated mutations in collective cell migration. Scientific Reports 11(1):10291.
Bhandary L, Bailey PC, Chang KT, Underwood KF, Lee CJ, Whipple RA, Jewell CM, Ory E, Thompson KN, Ju JA, Mathias TJ, Pratt SJP, Vitolo MI, Martin SS. (2021) Lipid tethering of breast tumor cells reduces cell aggregation during mammosphere formation. Scientific Reports 11(1):3214.
Pratt SJP, Hernández-Ochoa E, Martin SS. (2020) Calcium signaling: breast cancer’s approach to manipulation of cellular circuitry. Biophysical Reviews 12(6):1343-1359.
Ju J.A., Lee C.J., Thompson, K.N., Ory, E.C., Lee, R.M., Mathias, T.J., Pratt, S.J.P., Vitolo, M.I., Jewell, C.M., Martin, S.S. (2020) Partial thermal imidization of polyelectrolyte multilayer cell tethering surfaces (TetherChip) enables efficient cell capture and microtentacle fixation for circulating tumor cell analysis. Lab on a Chip 20(16):2872-2888.
Wong BS, Shah SR, Yankaskas CL, Bajpai VK, Wu PH, ChinD , Ifemembi B, ReFaey K, Schiapparelli P, Zheng X, Martin SS, Fan CM, Quiñones-Hinojosa A, Konstantopoulos, K.. A microfluidic cell-migration assay for the prediction of progression-free survival and recurrence time of patients with glioblastoma. Nature Biomedical Engineering 2020 Sep 28. doi: 10.1038/s41551-020-00621-9.
Pratt SJP, Lee RM, Chang KT, Hernández-Ochoa EO, Annis DA, Ory EC, Thompson KN, Bailey PC, Mathias TJ, Ju JA, Vitolo MI, Schneider MF, Stains JP, Ward CW, Martin SS (2020) Mechanoactivation of NOX2-generated ROS elicits persistent TRPM8 Ca2+ signals that are inhibited by oncogenic KRas. Proceedings of the National Academy of Sciences USA 20;117(42):26008-26019.
Yankaskas CL, Thompson KN, Paul CD, Vitolo MI, Mistriotis P, Mahendra A, Bajpai VK, Shea DJ, Manto KM, Chai AC, Varadarajan N, Kontrogianni-Konstantopoulos A, Martin SS, Konstantopoulos K. (2019) A microfluidic assay for the quantification of the metastatic propensity of breast cancer specimens. Nature Biomedical Engineering 2019 May 6. doi: 10.1038/s41551-019-0400-9.
Kallergi G, Aggouraki D, Zacharopoulou N, Stournaras C, Georgoulias V, Martin SS. (2018) Evaluation of α-tubulin, detyrosinated α-tubulin, and vimentin in CTCs: identification of the interaction between CTCs and blood cells through cytoskeletal elements. Breast Cancer Research 20(1):67.
Chakrabarti, K.R., Lindsay Hessler, L.K., Bhandary, L., and Martin, S.S. (2015). Molecular Pathways: New Signaling Considerations When Targeting Cytoskeletal Balance to Reduce Tumor Growth. Clinical Cancer Research 21(23):5209-14.
Boggs, A.E., Vitolo, M.I., Whipple, R.A., Charpentier, M.S., Goloubeva, O.G., Ioffe, O.B., Tuttle, K.C., Slovic, J., Lu, Y., Mills, G.B., Martin, S.S. (2015). α-tubulin acetylation elevated in metastatic and basal-like breast cancer cells promotes microtentacle formation, adhesion and invasive migration. Cancer Research 75(1):203-15.
Charpentier, M.S., Whipple, R.A., Vitolo, M.I., Boggs, A.E., Slovic, J., Thompson, K.N., Bhandary, L., Martin, S.S. (2014) Curcumin targets breast cancer stem-like cells with microtentacles that persist in mammospheres and promote reattachment. Cancer Research 74(4):1250-60.
Balzer, E.M., Whipple, R.A., Thompson, K., Boggs, A.E., Slovic, J., Cho, E.H., Matrone, M.A., Yoneda, T., Mueller, S.C., Martin, S.S. (2010). c-Src Differentially Regulates the Functions of Microtentacles and Invadopodia. Oncogene 29(48):6402-8.
Matrone, M.A., Whipple, R.A., Balzer, E.M., Martin, S.S. (2010). Microtentacles tip the balance of cytoskeletal forces in circulating tumor cells. Cancer Research 70(20):7737-41.
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., Martin, S.S. (2010) Epithelial-to-mesenchymal transition promotes tubulin detyrosination and microtentacles that enhance endothelial engagement. Cancer Research 70(20):8127-37 (Cover).
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., Martin, S.S. (2010) Metastatic breast tumors express increased tau, which promotes microtentacle formation and the reattachment of detached breast tumor cells. Oncogene 29(22):3217-27.
Vitolo, M.I., Weiss, M.B., Szmacinski, M., Tahir, K., Waldman, T., Park, B.H., Martin, S.S., Weber, D.J., Bachman, K.E. (2009) Deletion of PTEN promotes tumorigenic signaling, resistance to anoikis, and altered response to chemotherapeutic agents in Human Mammary Epithelial Cells. Cancer Research 69(21):8275-83.
Whipple, R.A., Balzer, E.M., Cho, E.H., Matrone, M.A., Yoon, J.R., Martin, S.S. (2008) Vimentin filaments support extension of tubulin-based microtentacles in detached breast tumor cells. Cancer Research 68(14):5678-88.
Martin, S.S., Ridgeway, A.G., Pinkas, J., Lu, Y., Reginato, M.J., Koh, E.Y., Michelman, M., Daley, G.Q., Brugge, J.S., Leder, P. (2004). A cytoskeleton-based functional genetic screen identifies Bcl-xL as an enhancer of metastasis,but not primary tumor growth. Oncogene 23:4641-5.
Martin, S.S., Leder, P. (2001). Human mammary epithelial cells undergo apoptosis following actin depolymerization that is independent of attachment and rescued by Bcl-2. Molecular and Cellular Biology 21(19): 6529-36.
Martin, S.S., Haruta, T., Morris, A.J., Klippel, A., Williams, L.T., Olefsky J.M. (1996). Activated Phosphatidylinositol 3-Kinase Is Sufficient to Mediate Actin Rearrangement and GLUT4 Translocation in 3T3-L1 Adipocytes. Journal of Biological Chemistry 271(30): 17605-8.
Apoptosis and breast tumor metastasis
Nearly 90% of human solid tumors arise from epithelial cells as carcinomas, so we are interested in studying the role of epithelial cell survival in tumor metastasis. Many epithelial cell types succumb to apoptotic cell death upon detachment from the extracellular matrix. The resulting survival pressure enforces an important physiological control on cellular location within a tissue. This principle helps maintain epithelial barrier function and ensures the death of cells that detach during processes such as mammary gland involution, embryonic cavitation and the turnover of cells lining the gut and skin. The propensity of epithelial cells to die after detachment is also thought to limit the metastatic dissemination of epithelial tumors.
We have demonstrated that human mammary epithelial cells must spread and adopt a distinct cell shape in order to survive after binding the extracellular matrix. Disrupting actin-mediated cell spreading rapidly causes cell death. Metastatic breast tumor cell lines are not sensitive to this shape-dependent cell death, and tolerate long periods of cell rounding without significant apoptosis. Such indifference to altered cell shape may allow malignant cells to tolerate the gross cytoskeletal disruptions often observed in metastatic tumors. Interestingly, resistance to cell death will not cause primary tumor growth, but greatly enhances metastatic spread when combined with an activated oncogene.
These results may help explain why so many mouse models of breast cancer fail to metastasize. A simple hypothesis would be that two classes of oncogenes exist, those that induce primary tumor growth, and those that only enhance metastasis but do not induce active growth (like Bcl-2 or Bcl-xL). For this reason, many of the classical methods for identifying oncogenes, such as soft agar colony formation and nude mouse injection, may have failed to isolate metastasis-enhancing oncogenes that allow resistance to cell shape change without directly enhancing growth.
Functional genomic screening for metastatic regulators
Since growth-based assays may not identify survival factors that contribute to metastatic spread, we developed an in vitro assay to select directly for resistance to shape-dependent cell death. Infection of human mammary epithelial cells with a retroviral expression library from a metastatic breast tumor cell line allowed the isolation of genes conferring a survival advantage. In addition to this genetic approach, we are using proteomics to identify new substrates of the death-associated protein kinase (DAPK). Expression of DAPK is often lost in metastatic tumor cells, but its cellular substrates remain unknown. Large-scale in vitro kinase screening of a human expressed protein array identified 15 new in vitro substrates of DAPK, and we are assessing their function in cells. Finally, we are filtering available datasets from breast cancer patients to computationally identify survival genes that may confer a higher risk of metastasis.
In vivo tumor imaging
In order to measure the effects of the identified genes on breast tumor metastasis, we are using in vivo imaging of transplanted tumor cells. Luciferase-expressing mouse mammary epithelial cells are used to generate cell lines stably expressing the identified survival oncogenes. Tumor growth and metastatic spread can be measured by injecting these cells into living mice and measuring the bioluminescence from the tumor cells. Since this measurement does not require sacrifice of the mice, studies addressing tumor dormancy and therapeutic response can be conducted more accurately and with far fewer mice. More importantly, since our prediction is that survival oncogenes will allow tumor spread without inducing active growth, bioluminescence allows us to follow the fate of tumor cells that fail to grow but are not eradicated. Successful treatment of such persistent and dormant tumor cells is critical for patients, since many die from recurrent metastatic disease, rather than the primary tumor.
- Human mammary epithelial cells (MCF10A) attaching to extracellular matrix. Cells are stained fluorescently for actin (red), microtubules (green) and DNA (blue). Dynamic rearrangement of the actin cytoskeleton is essential for both cell spreading and survival.
- In vivo imaging of transplanted breast tumor cell lines in a single mouse. Real-time tracking and measurement of cells is possible for those tumors that grow (MEK/Bcl2) as well as those that lie dormant (EpH4 or Bcl2). At these early time points, none of the tumors are palpable, but clear differences can still be detected by bioluminescence after injection of luciferin.