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Michael M. Shen, PhD

  • Professor of Medical Sciences (in Medicine)
  • Professor of Genetics & Development
  • Director of Graduate Studies, Department of Genetics & Development
Michael M. Shen, PhD

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.

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

Education & Training

  • BA, 1984 Biochemical Sciences, Harvard University
  • PhD, 1988 Genetics, Cambridge University
  • Fellowship: Harvard Medical School

NIH Grants

  • PREDOCTORAL TRAINING GRANT IN GENETICS AND DEVELOPMENT (Federal Gov)

    Jul 1 2016 - Jun 30 2021

    SYSTEMS ANALYSIS OF MOUSE GASTRULATION (Federal Gov)

    Jul 10 2016 - Apr 30 2021

    INVESTIGATING THE CELL OF ORIGIN OF BLADDER CANCER (Federal Gov)

    Apr 1 2015 - Mar 31 2020

    INVESTIGATION OF A PUTATIVE PROSTATE STEM CELL NICHE (Federal Gov)

    Sep 1 2016 - Aug 31 2019

    ANALYSIS OF DRUG RESPONSE IN ORGANOIDS AND MOUSE MODELS (Federal Gov)

    Jul 1 2016 - Jun 30 2019

    CANCER CENTER SUPPORT GRANT (Federal Gov)

    Jul 1 2014 - Jun 30 2019

    CULTURE OF PATIENT-DERIVED BLADDER CANCER ORGANOIDS (Private)

    Jul 1 2016 - Jun 30 2018

    INVESTIGATION OF LUMINAL STEM CELLS AND CASTRATION RESISTANCE IN PROSTATE CANCER (Federal Gov)

    Apr 1 2015 - Mar 31 2018

    PROGENITOR CELLS OF THE MOUSE PROSTATE EPITHELIUM (Federal Gov)

    Jul 1 2006 - Mar 31 2018

    MODELING HUMAN PROSTATE CANCER BY CELLULAR REPROGRAMMING (Federal Gov)

    Jul 1 2015 - Dec 31 2017

    IDENTIFICATION OF MASTER REGULATORS OF ADVANCED AND CASTRATE-RESISTANT PROSTRATE CANCER UNDER TREATMENT WITH ABIRATERONE. (Federal Gov)

    Sep 30 2013 - Sep 29 2017

    IDENTIFICATION AND VALIDATION OF MASER REGULATORS OF CASTRATION RESISTANT PROSTATE CANCER (Federal Gov)

    Sep 1 2015 - Aug 31 2017

    EPIGENETIC REGULATION OF BLADDER CANCER PROGRESSION (Private)

    Jul 15 2015 - Jul 14 2017

    MOLECULAR MECHANISMS OF PROSTATE CANCER INITIATION (Federal Gov)

    Sep 16 2011 - Feb 28 2017

    TARGETING GENOMIC INSTABILITY IN SPOP MUTANT PROSTATE CANCER (Private)

    Jan 1 2015 - Dec 31 2016

    INVESTIGATION OF HUMAN PROSTATE CANCER PROGRESSION AND TREATMENT RESPONSE USING A NOVEL GENETICALLY ENGINEERED CULTURE MODEL (Federal Gov)

    Aug 19 2014 - Aug 18 2016

    INVESTIGATION OF CYSVIEW CYTOTOXICITY FOR HUMAN BLADDER ORGANOIDS (Private)

    Aug 1 2015 - Jul 31 2016

    NATIONAL CENTER: MULTISCALE ANALYSIS OF GENOMIC AND CELLULAR NETWORKS (MAGNET) (Federal Gov)

    Sep 26 2005 - Jul 31 2016

    ELUCIDATION OF CANCER PATHWAYS AND DRUGGABLE TARGETS USING MOUSE MODELS (Federal Gov)

    Sep 30 1999 - Jul 31 2015

    HIPPO SIGNALING IN PROSTATE REGENERATION AND CANCER (Federal Gov)

    Sep 1 2012 - Aug 31 2014

    A NOVEL MODEL SYSTEM FOR ASSAYING DRUG RESPONSES OF HUMAN PROSTATE CANCER (Private)

    Jul 1 2013 - Jun 30 2014

    DIRECTED DIFFERENTIATION AND TRANSDIFFERENTATION TO PROSTATE AND BLADDER EPITHELIA (Private)

    Jul 1 2012 - Jun 30 2014

    FUNCTIONAL ANALYSIS OF E-CADHERIN IN PROSTATE CANCER PROGRESSION (Federal Gov)

    Mar 1 2012 - Feb 28 2014

    IDENTIFICATION AND ANALYSIS OF PROSTATE TUMOR INITIATING CEL LS (NY State Gov)

    Sep 1 2010 - Aug 31 2013

    IDENTIFICATION OF MASTER REGULATORS FOR STEM CELL PLURIPOTEN CY AND SELF-RENEWAL (NY State Gov)

    Sep 1 2010 - Aug 31 2013

    FUNCTIONAL ANALYSIS OF ANDROGEN RECEPTOR IN PROSTATE EPITHELIAL STEM CELLS (Federal Gov)

    Jun 1 2011 - Jun 30 2013

    LINEAGE ANALYSIS OF CELLS OF ORIGIN FOR PROSTATE CANCER (Federal Gov)

    Jun 1 2011 - May 31 2013

    FUNCTIONAL ANALYSIS OF CRIPTO IN MOUSE EMBRYOGENESIS (Federal Gov)

    Apr 1 1998 - Apr 30 2013

    NEXT-GENERATION MOUSE MODELS FOR STUDYING PROSTATE CANCER IN ITIATION AND PROGRESSION (Federal Gov)

    Jun 1 2009 - Jun 30 2012

    IDENTIFICATION OF MASTER REGULATORS FOR STEM CELL PLURIPOTEN CY AND SELF-RENEWAL (Federal Gov)

    Apr 1 2010 - Mar 31 2012

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. 

For a complete list of publications, please visit PubMed.gov