Shree Ram Singh, Ph.D.
Shree Ram  Singh, Ph.D.
Staff Scientist

Stem cells have an inherent ability to self-renew and to differentiate into several specialized cell types as well as control the maintenance of our tissues and organs. Failure of such maintenance results in several degenerative diseases and cancer. Stem cells have recently attracted significant attention, mainly because of their potential medical benefits in the fields of therapeutic cloning and regenerative medicine. Our current research is directed toward understanding the molecular genetic mechanism by which stem cells regulate tissue homeostasis, regeneration, and tumorigenesis. We are utilizing Drosophila and mouse models to understand the above mechanisms. Specifically, we are using adult testis, kidney and gastrointestinal tissues to characterize the genes/signaling pathways that regulate stem cell behavior and tumor formation. The knowledge gained from investigating stem cell regulation in Drosophila and mouse models will provide a basis for understanding how human adult stem cells respond during normal and pathological conditions.

Areas of Expertise
1) stem cells, 2) cancer stem cells, 3) microRNAs in cancer, 4) cancer metabolism, 5) Drosophila stem cells, 6) tumor microenvironment

Contact Info

Shree Ram Singh, Ph.D.
Center for Cancer Research
National Cancer Institute
Building 560, Room 12-15
Frederick, MD 21702-1201
301-846-7331
singhshr@mail.nih.gov

Stem cells are undifferentiated cells and play a critical role in tissue development, homeostasis, and regeneration. Stem cells self-renewal divisions are controlled by intrinsic and extrinsic factors. Failure of stem cells function in tissue maintenance results in degenerative diseases, on the other hand, the overproliferation of stem cells results in tumor development (Singh et al., Cell Res 2005; Singh et al., J Cell Mol Med 2011; Singh, Curr Med Chem 2012; Singh, Cancer Lett 2013). Our current research is directed toward understanding the molecular genetic mechanisms by which stem cells regulate tissue homeostasis, regeneration, and tumorigenesis. We are utilizing Drosophila and mouse models to understand the above mechanisms.

In 2006, we  identified a novel gene, namely GEF (a small GTPase guanine nucleotide exchange factor), and demonstrated that a Rap-GEF/Rap signaling pathway regulates stem cell anchoring to the niche and organ formation by regulating DE-cadherin-mediated cell adhesion (Wang et al., Dev Cell 2006; Singh et al., Dev Growth Differ 2006). Further, we demonstrated that the Drosophila homologue of the human tumor suppressor gene BHD regulates male germline stem cells maintenance and functions downstream of the JAK/STAT and Dpp signal transduction pathways. These findings suggest that BHD regulates tumorigenesis by modulating stem cells in human (Singh et al., Oncogene 2006). Furthermore, we also demonstrated that germline and somatic stem cells coordinate their self-renewal and differentiation through the JAK/STAT signaling pathway during Drosophila spermatogenesis (Singh et al., J Cell Physiol 2010).

Our lab identified kidney stem cells in Drosophila and characterized the signaling pathways that are responsible for maintenance of these stem cells in renal tubules (Singh et al., Cell Stem Cell 2007; Singh and Hou, JASN 2008; Singh and Hou, J Exp Biol 2008; Zeng et al.,J Cell Physiol 2010). Recently, we also identified gastric stem cells in the adult Drosophila (Singh et al., Cell Cycle 2011). We further found that JAK-STAT signaling regulates gastric stem cell proliferation, Wingless signaling regulates gastric stem cell self-renewal, and Hedgehog signaling regulates gastric stem cell differentiation.

In the last few years, we have been focusing on identifying the genes responsible for gastrointestinal stem cell self-renewal and differentiation. Recently, we found that JAK-STAT signaling controls ISC proliferation and this ability is negatively regulated by Notch, at least through transcriptional control of the JAK-STAT signaling ligand, unpaired (Liu et al., J Cell Biochem 2010). More recently, we finished a genome-wide RNAi screen in Drosophila gastrointestinal tissues (Zeng et al., Cell Reports 2015) as well as in Drosophila testis and identified novel regulators in  these two tissue systems. We are currently focusing on characterizing these genes. In addition, we also developed immunofluorescence labeling, and in situ hybridization techniques for the identification and  characterization of stem cells and differentiated cells in different Drosophila tissues (Singh and Hou, Methods Mol Biol 2008; Singh et al., Methods Mol Biol 2013).

In collaborations, we have investigated the differentiation potential of osteoarthritic chondrocytes (OC) into iPSCs using defined transcription factors and explored the possibility of using these OC-derived iPSCs for chondrogenesis. We found that iPSCs could be generated from OCs using defined factors and that in vitro co-culture of TGF-β1-transfected OC-derived iPSCs with articular cartilages (ACs) in alginate matrix results in significantly improved chondrogenesis of iPSCs. In addition, in vivo study also revealed the obvious cartilage tissue formed in the co-culture of TGF-β1- transfected OC-derived iPSCs with ACs in alginate matrix. This combinational strategy will promote the use of iPSC-derived tissue in tissue engineering. Further, we are also focusing on the PDX model in colon cancer (Seol et al., Cancer Lett 2014) as well as the role of microRNAs in metabolism and tumor development (Seol et al., Cancer Lett, 2014; Kim et al., Cancer Lett 2015; Chan et al., Cancer Lett 2015; Singh et al., Cancer Lett 2015).

 

 

 

Scientific Focus Areas:
Cancer Biology, Cell Biology, Developmental Biology, Genetics and Genomics, Stem Cell Biology
  1. Kim S, Rhee JK, Yoo HJ, Lee HJ, Lee EJ, Lee JW, Yu JH, Son BH, Gong G, Kim SB, Singh SR, Ahn SH, Chang S
    Cancer Lett. 357: 488-497, 2015. [ Journal Article ]
  2. Zeng X, Han L, Singh SR, Liu H, Neumüller RA, Yan D, Hu Y, Liu Y, Liu W, Lin X, Hou SX
    Cell Rep. 10: 1226-1238, 2015. [ Journal Article ]
  3. Seol HS, Akiyama Y, Shimada S, Lee HJ, Kim TI, Chun SM, Singh SR, Jang SJ
    Cancer Lett. 353: 232-241, 2014. [ Journal Article ]
  4. Wei Y, Zeng W, Wan R, Wang J, Zhou Q, Qiu S, Singh SR
    Eur Cell Mater. 23: 1-12, 2012. [ Journal Article ]
  5. Singh SR, Liu W, Hou SX.
    Cell Stem Cell. 1: 191-203, 2007. [ Journal Article ]

Dr. Shree Ram Singh obtained his Ph.D. in genetics from the Department of Zoology, Banaras Hindu University, India in 2001. Dr. Singh was a guest scientist at the Department of Molecular Cell Biology Biocenter, Johann Wolfgang Goethe University, Frankfurt, Germany in 1998 and in 2001 he received a UNESCO Biotechnology Action Council (BAC) fellowship at the Department of Plant Molecular Biology Biocenter, Johann Wolfgang Goethe University. Dr. Singh pursued his postdoctoral research studies at the University of Haifa, Israel, and at the National Cancer Institute at Frederick. Since 2011, he has served as a staff scientist at National Cancer Institute at Frederick.

Name Position
Jae Eun Lee Student Intern (Werner H. Kirsten)
Jacob Manley Student Intern (Werner H. Kirsten)

Research

Stem cells are undifferentiated cells and play a critical role in tissue development, homeostasis, and regeneration. Stem cells self-renewal divisions are controlled by intrinsic and extrinsic factors. Failure of stem cells function in tissue maintenance results in degenerative diseases, on the other hand, the overproliferation of stem cells results in tumor development (Singh et al., Cell Res 2005; Singh et al., J Cell Mol Med 2011; Singh, Curr Med Chem 2012; Singh, Cancer Lett 2013). Our current research is directed toward understanding the molecular genetic mechanisms by which stem cells regulate tissue homeostasis, regeneration, and tumorigenesis. We are utilizing Drosophila and mouse models to understand the above mechanisms.

In 2006, we  identified a novel gene, namely GEF (a small GTPase guanine nucleotide exchange factor), and demonstrated that a Rap-GEF/Rap signaling pathway regulates stem cell anchoring to the niche and organ formation by regulating DE-cadherin-mediated cell adhesion (Wang et al., Dev Cell 2006; Singh et al., Dev Growth Differ 2006). Further, we demonstrated that the Drosophila homologue of the human tumor suppressor gene BHD regulates male germline stem cells maintenance and functions downstream of the JAK/STAT and Dpp signal transduction pathways. These findings suggest that BHD regulates tumorigenesis by modulating stem cells in human (Singh et al., Oncogene 2006). Furthermore, we also demonstrated that germline and somatic stem cells coordinate their self-renewal and differentiation through the JAK/STAT signaling pathway during Drosophila spermatogenesis (Singh et al., J Cell Physiol 2010).

Our lab identified kidney stem cells in Drosophila and characterized the signaling pathways that are responsible for maintenance of these stem cells in renal tubules (Singh et al., Cell Stem Cell 2007; Singh and Hou, JASN 2008; Singh and Hou, J Exp Biol 2008; Zeng et al.,J Cell Physiol 2010). Recently, we also identified gastric stem cells in the adult Drosophila (Singh et al., Cell Cycle 2011). We further found that JAK-STAT signaling regulates gastric stem cell proliferation, Wingless signaling regulates gastric stem cell self-renewal, and Hedgehog signaling regulates gastric stem cell differentiation.

In the last few years, we have been focusing on identifying the genes responsible for gastrointestinal stem cell self-renewal and differentiation. Recently, we found that JAK-STAT signaling controls ISC proliferation and this ability is negatively regulated by Notch, at least through transcriptional control of the JAK-STAT signaling ligand, unpaired (Liu et al., J Cell Biochem 2010). More recently, we finished a genome-wide RNAi screen in Drosophila gastrointestinal tissues (Zeng et al., Cell Reports 2015) as well as in Drosophila testis and identified novel regulators in  these two tissue systems. We are currently focusing on characterizing these genes. In addition, we also developed immunofluorescence labeling, and in situ hybridization techniques for the identification and  characterization of stem cells and differentiated cells in different Drosophila tissues (Singh and Hou, Methods Mol Biol 2008; Singh et al., Methods Mol Biol 2013).

In collaborations, we have investigated the differentiation potential of osteoarthritic chondrocytes (OC) into iPSCs using defined transcription factors and explored the possibility of using these OC-derived iPSCs for chondrogenesis. We found that iPSCs could be generated from OCs using defined factors and that in vitro co-culture of TGF-β1-transfected OC-derived iPSCs with articular cartilages (ACs) in alginate matrix results in significantly improved chondrogenesis of iPSCs. In addition, in vivo study also revealed the obvious cartilage tissue formed in the co-culture of TGF-β1- transfected OC-derived iPSCs with ACs in alginate matrix. This combinational strategy will promote the use of iPSC-derived tissue in tissue engineering. Further, we are also focusing on the PDX model in colon cancer (Seol et al., Cancer Lett 2014) as well as the role of microRNAs in metabolism and tumor development (Seol et al., Cancer Lett, 2014; Kim et al., Cancer Lett 2015; Chan et al., Cancer Lett 2015; Singh et al., Cancer Lett 2015).

 

 

 

Scientific Focus Areas:
Cancer Biology, Cell Biology, Developmental Biology, Genetics and Genomics, Stem Cell Biology

Publications

  1. Kim S, Rhee JK, Yoo HJ, Lee HJ, Lee EJ, Lee JW, Yu JH, Son BH, Gong G, Kim SB, Singh SR, Ahn SH, Chang S
    Cancer Lett. 357: 488-497, 2015. [ Journal Article ]
  2. Zeng X, Han L, Singh SR, Liu H, Neumüller RA, Yan D, Hu Y, Liu Y, Liu W, Lin X, Hou SX
    Cell Rep. 10: 1226-1238, 2015. [ Journal Article ]
  3. Seol HS, Akiyama Y, Shimada S, Lee HJ, Kim TI, Chun SM, Singh SR, Jang SJ
    Cancer Lett. 353: 232-241, 2014. [ Journal Article ]
  4. Wei Y, Zeng W, Wan R, Wang J, Zhou Q, Qiu S, Singh SR
    Eur Cell Mater. 23: 1-12, 2012. [ Journal Article ]
  5. Singh SR, Liu W, Hou SX.
    Cell Stem Cell. 1: 191-203, 2007. [ Journal Article ]

Biography

Dr. Shree Ram Singh obtained his Ph.D. in genetics from the Department of Zoology, Banaras Hindu University, India in 2001. Dr. Singh was a guest scientist at the Department of Molecular Cell Biology Biocenter, Johann Wolfgang Goethe University, Frankfurt, Germany in 1998 and in 2001 he received a UNESCO Biotechnology Action Council (BAC) fellowship at the Department of Plant Molecular Biology Biocenter, Johann Wolfgang Goethe University. Dr. Singh pursued his postdoctoral research studies at the University of Haifa, Israel, and at the National Cancer Institute at Frederick. Since 2011, he has served as a staff scientist at National Cancer Institute at Frederick.

Team

Name Position
Jae Eun Lee Student Intern (Werner H. Kirsten)
Jacob Manley Student Intern (Werner H. Kirsten)