Researcher’s Profile

Michael M. Shen, PhD

Director of Graduate Studies, Department of Genetics & Development
Quote: 

Molecular mechanisms of pattern formation and cellular differentiation during mouse embryogenesis; Organogenesis and regeneration of the prostate gland; Mouse models of prostate cancer.

Publications: 
1. Wang, X., Kruithof-de Julio, M., Economides, K. D., Walker, D., Yu, H., Halili, M. V., Hu, Y.-P., Price, S. M., Abate-Shen, C., and Shen, M. M.: (2009) A luminal epithelial stem cell that is a cell of origin for prostate cancer.  Nature  461: 495-500. 2. Shen, M. M., and Abate-Shen, C. (2010). Molecular genetics of prostate cancer: new prospects for old challenges. Genes Dev. 24: 1967-2000.  3. Kruithof-de Julio, M., Alvarez, M. J., Galli, A., Chu, J., Price, S. M., Califano, A., and Shen, M. M.: (2011) Regulation of extraembryonic endoderm stem cell differentiation by Nodal and Cripto signaling.  Development  138: 3885-3895  4. Wang, Z. A., Mitrofanova, A., Bergren, S. K., Abate-Shen, C., Cardiff, R. D., Califano, A., and Shen, M. M.: (2013) Lineage analysis of basal epithelial cells reveals their unexpected plasticity and supports a cell of origin model for prostate cancer heterogeneity.  Nat. Cell Biol.  15: 274-283  5. Wang, Z. A., Toivanen, R., Bergren, S. K., Chambon, P., and Shen, M. M.: (2014) Luminal cells are favored as the cell of origin for prostate cancer.  Cell Rep.  8: 1339-1346  6. Chua, C. W., Shibata, M., Lei, M., Toivanen, R., Barlow, L. J., Bergren, S. K., Badani, K. K., McKiernan, J. M., Benson, M. C., Hibshoosh, H., and Shen, M. M.: (2014) Single luminal epithelial progenitors can generate prostate organoids in culture.  Nat. Cell Biol.  16: 951-961  7. Toivanen, R., Mohan, A., and Shen, M. M. (2016). Basal progenitors contribute to repair of the prostate epithelium following induced luminal anoikis. Stem Cell Rep. 6: 660-667.  8. Toivanen, R., and Shen, M. M. (2017). Prostate organogenesis: tissue induction, hormonal regulation and cell type specification. Development 144, 1382-1398. 
Body: 

Our laboratory investigates the regulation of pattern formation and organogenesis during vertebrate development, and how these processes are disrupted in cancer initiation and progression. These studies primarily utilize experimental approaches involving genetically-engineered mice, but also employ cell culture and biochemical approaches to investigate molecular mechanisms.

In the first major area of interest in our laboratory, we are investigating the biological functions of Nodal, a member of the Transforming Growth Factor-beta (TGFβ) family that is essential for multiple critical processes during formation of the vertebrate body plan, including anterior-posterior and left-right axis specification, as well as formation of the germ layers during gastrulation. We have been particularly interested in the regulation of Nodal signaling at the extracellular level by EGF-CFC co-receptors and Lefty soluble inhibitors, using approaches ranging from phenotypic analyses of gene-targeted mouse embryos to biochemical studies of protein interactions. In ongoing studies, we are continuing work on the establishment of the anterior-posterior axis as well as analyses of signaling pathways that govern pre-gastrulation development. We are also pursuing new projects on the molecular regulation of self-renewal and differentiation of stem cell types derived from the peri-implantation mouse embryo.

In a second primary area of research, our laboratory is investigating the molecular mechanisms of tissue organogenesis and their relationship to tumor initiation and progression, through the generation and analysis of mouse models of prostate cancer. Many of our studies have focused on functional analyses of the homeobox gene Nkx3.1, which is essential for normal prostate epithelial differentiation and is inactivated during human prostate cancer initiation. In current studies, we are examining the role of prostate epithelial progenitor cells in prostate organogenesis and regeneration, as well as cancer initiation. Using targeted conditional and inducible mice for lineage-marking, we have identified a novel epithelial progenitor cell population that can also serve as a cell type of origin for prostate cancer. Primary objectives of our ongoing work are to identify key signaling pathways that regulate proliferation and differentiation of these candidate stem cells, and to determine their relationship to putative cancer stem cells during carcinogenesis. Further studies will examine the roles of analogous cell populations in the genesis of human prostate cancer, and assess the abilities of potential therapeutics to target these progenitor cells.