Video: Dr. Martin's Research on Microtentacles in Circulating Breast Cancer Cells
Tumor cells are able to tolerate detachment and gross disruptions of cell shape without dying. Normal epithelial cells quickly die by apoptosis under similar circumstances. Since nearly 90% of human solid tumors arise as carcinomas from epithelial cells, we are interested in studying how breast tumor cells become resistant to this form of cell death. We have recently shown that resistance to apoptosis greatly increases the metastatic potential of mammary epithelial cells, but does not induce primary tumor formation. Genes responsible for increased metastatic spread may therefore remain undetectable by growth-based assays.
We have observed that metastatic breast tumor cells resist apoptosis upon disruption of their actin cytoskeleton, while normal epithelial cells die. We used this principle to perform a genetic screen for determinants of apoptotic resistance in metastatic breast tumor cells. Combining this approach with proteomic kinase substrate screening and computational biology, we have identified several factors with potentially novel roles in breast tumor metastasis. We are currently examining the cell biology of these genes and measuring their effect on metastasis in mice. Since apoptotic resistance could yield extended tumor dormancy, rather than active growth, we are using a bioluminescence technique to image tumor cell survival in living mice.
Pinkas, J., Martin, S.S. and Leder, P. (2004) Bcl-2-mediated cell survival promotes metastasis of EpH4-MEKDD mammary epithelial cells. Molecular Cancer Research 2:551-6.
Martin, S.S., Ridgeway, A.G., Pinkas, J., Lu, Y., Reginato, M.J., Koh, E.Y., Michelman, M., Daley, G.Q., Brugge, J.S., and 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. and Vuori, K. (2004). Regulation of Bcl-2 proteins during anoikis and amorphosis. BBA Molecular Cell Research 1692:145-57.
Martin, S.S. and Leder, P. (2001). Human MCF10A mammary epithelial cells undergo apoptosis following actin depolymerization that is independent of attachment and rescued by Bcl-2. Mol. Cell. Biol 21(19):6529-6536.