Acquisition of invasiveness and metastatic powers by cancer cells
The ability of cancer cells to invade and metastasize is determined by the genetic changes that these cells have undergone during the course of multi-step tumorigenesis. In addition, the microenvironment of the cancer cell is a strong determinant of whether or not it acquires the capabilities to invade and metastasize. Thus, during the course of primary tumor formation, the cells in a carcinoma will recruit a complex array of mesenchymal cells from the host that together form the tumor-associated stroma. Prominent among these are fibroblasts and myofibroblasts. As tumor progression proceeds, the stromal cells create a "reactive stroma" that releases a variety of signals that impinge on the carcinoma cells and induce changes in their phenotype. We have begun to examine the nature of the signals that are released by this stroma and serve to induce the epithelial-mesenchymal transition (EMT), a profound change in cell phenotype that causes immotile epithelial cells to acquire traits such as motility, invasiveness, and resistance to apoptosis. These signals serve to induce expression of a series of transcription factors that are capable, in turn of inducing the EMT. A significant amount of our research is focused on the nature of these heterotypic signals and how they act, in concert, to induce expression of the EMT-inducing transcription factors in nearby carcinoma cells.
The EMT and the stem-cell state
Our research has indicated that the act of inducing an EMT (epithelial-mesenchymal transition) in normal and neoplastic mammary epithelial cells results in cells that have acquired many of the attributes of stem cells. Included among these are the expression of cell-surface markers that enable the isolation of stem-cell-like cells. Research into the nature of the EMT-inducing signals (see above) is likely to shed light, as well, on the signals within a stem-cell niche that enable the formation of stem cells and their perpetuation in the stem-cell state. Moreover, by discovering the nature of the stem-cell-inducing signals, we may be able to convert differentiated epithelial cells into epithelial stem cells, which may have important implications for the regeneration of certain epithelial tissues. We believe that the EMT is induced by a group of collaborating signaling molecules. Accordingly, this research is exploring the identities of a variety of signaling proteins that function, in aggregate, to induce an EMT in cancer cells.
Master regulators of the EMT
We have been working with a series of 6-7 transcription factors (TFs) that are expressed transiently during embryogenesis when they program the EMT. These TFs are found to be expressed by invasive and metastatic cells, on which they confer many of the cell phenotypes of high-grade malignancy. In fact, these TFs rarely act alone, but instead intercommunicate and form a complex circuitry that enables them to collaborate to induce the EMT. We are attempting to understand the organization of the signaling circuitry that enable the various EMT-inducing TFs to induce this profound cell-biological change in normal and neoplastic cells. In addition, we are studying the downstream consequences of the actions of these TFs in terms of the genes whose expression they induce and the cell-biological consequences of this induction. We anticipate that gene expression array analyses will allow us to define a core EMT gene expression program that should prove important in understanding the biochemical mechanisms of cancer cell invasion and metastasis and, at the same time, provide indications of useful diagnostic markers to indicate the presence of cells that possess malignant potential within tumors.
Godar, S., Ince. T.A., Bell, G.W., Feldser, D., Donaher, J.L., Bergh, J., Liu, A., Miu, K., Watnick, R.S., Reinhardt, F., McAllister, S.S., Jacks, T. and Weinberg. R.A. Growth-inhibitory and tumor suppressive functions of p53 depend on its repression of CD44 expression. Cell 134:62-73 (2008).
Mani S.A., Guo W., Liao M.J. et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell, 133:704-15 (2008).
McAllister S.S., Gifford A.M., Greiner A.L., et al. Systemic endocrine instigation of indolent tumor growth requires osteopontin. Cell, 133:994-1005 (2008).
Karnoub, A.E., Dash, A.B., Vo, A.P., Sullivan, A., Brooks, M.A., Bell, G.W., Richardson, A. Polyak, K., Tubo, R., and Weinberg, R.A. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature, 449:557-563 (2007).
Ma, L., Teruya-Feldstein, J., and Weinberg, R.A. Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature, 449:682-688 (2007).
Ince, T. A., Richardson, A.L., Saitoh, M., Bell, G.W., Godar, S., Karnoub, A., Iglehart, J.D., and Weinberg, R.A. Transformation of different human breast epithelial cell types leads to distinct tumor phenotypes. Cancer Cell 12, 160-170 (2007).
Gupta, P.B., Kuperwasser, C., Brunet, J-P., Ramaswamy, S., Kuo, W-L., Gray, J.W., Naber, S.P., and Weinberg, R.A. The melanocyte differentiation program predisposes to metastasis after neoplastic transformation. Nature Genetics 37, 1047-1054 (2005).
Orimo, A., Gupta, P.B., Sgroi, D.C., Arenzana-Seisdedos, F., Delaunay, T., Rizwan, N., Carey, V.J., Richardson, A.L., and Weinberg, R.A. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell, 121: 335-348 (2005).