McMaster University

McMaster University

Sheila K. Singh

Sheila K. SinghScientist

McMaster Stem Cell and Cancer Research Institute (SCC-RI)

Associate Professor, Surgery (Division of Neurosurgery), Biochemistry and Pediatrics

Dr. Sheila Singh joined the McMaster Stem Cell and Cancer Research Institute in July 2007. Prior to her arrival at McMaster, Sheila completed a PhD at the Hospital for Sick Children. She obtained her degree within the Surgeon Scientist Training Program at the University of Toronto, where she completed her residency and fellowship training specializing in pediatric neurosurgery. She holds a Tier 2 Canada Research Chair in Human Cancer Stem Cell Biology.

During her PhD, Dr. Singh first identified an abnormal stem cell that may drive the formation of brain tumours. Using the cell surface protein CD133, Dr. Singh has characterized a rare subpopulation of brain tumour cells that exclusively generate a replica of the patient's tumour and exhibit self-renewal ability in vivo through serial retransplantation.

Dr. Singh's lab applies a developmental neurobiology framework to the study of brain tumorigenesis. Building upon previously applied and refined cell culture techniques developed for the isolation of normal neural stem cells (NSC) to brain tumours, and development of a xenograft model to efficiently study brain tumour initiating cell (BTIC) activity, Dr. Singh's lab aims to understand the molecular mechanisms that govern BTIC self-renewal. Her program applies fluorescent activated cell sorting to the prospective isolation of different classes of BTICs, and xenograft modeling coupled with either transgenic overexpressing BTICs or siRNA knockdown BTICs to respectively overexpress or underexpress key molecular mediators (such as Bmi1) in the BTIC population. This work will permit a functional characterization of stem cell signaling pathways that are disrupted during the possible transformation of the NSC to a BTIC.

Dr. Singh applies these stem cell biology techniques in an effort to further characterize the heterogeneity that exists in brain tumours. Dr. Singh is currently studying the regulation of BTIC signaling pathways in glioblastoma, brain metastases and childhood medulloblastoma, with an ultimate goal of selectively targeting the BTIC with appropriately tailored drug and molecular therapies.

Current Projects

  • The role of Bmi1 in Glioblastoma BTIC self-renewal and tumour maintenance
    This work aims to elucidate the role of the master stem cell regulatory gene Bmi1 in brain tumorigenesis, and to discover the ways in which the conserved Bmi-1-driven signaling pathway may drive malignancy and metastatic potential. By profiling the epigenome of stem cell populations in GBM, we hope to map a comprehensive gene network governed by Bmi1. This network will reveal the function of Bmi1 in BTICs and in brain tumorigenesis, providing future selective therapeutic targets for children and adults with brain tumours.
  • The role of developmental signaling pathways in medulloblastoma stem cells
    Since developmental signaling pathways such as Wnt and key regulators of stem cell self-renewal such as Bmi1, Sox2 and FoxG1 are clearly important in regulating stem cell self-renewal and proliferation, we are combining recent molecular subtyping analysis of this tumour with modulation of these key stem cell signaling pathways in human medulloblastoma BTICs. Identification of a stem cell signature and modulation of critical selectively active stem cell signaling pathways in MB patients may help to develop specific, individualized therapy targeted against BTICs. Translation of this research into experimental therapeutics that specifically target the aberrant signal transduction machinery in MB BTICs will hopefully lead to an improved risk-benefit profile for current survivors, and to an overall improved survivorship for all MB patients.
  • Identification and characterization of brain metastasis-initiating cells from metastatic lung cancer
    Brain metastases (BMs) are common in adults suffering from a variety of primary cancers, such as lung, breast, and colon cancers. Their invasive nature and ability to escape current treatments predicts uniformly poor patient outcome, with a median survival time of only months. Despite their frequency and severity, very little research exists on BMs, nor is there an appropriate experimental model with which to study them. We hypothesize BMs contain a subpopulation of CSC-like cells capable of exclusive initiation and maintenance of the tumour, termed brain metastasis-initiating cells (BMICs). Our published primary brain TIC (BTIC) model provides an established platform that can be applied to the novel study of BMICs. We are identifying a putative BMIC population in lung-to-brain metastases using known and novel CSC and metastasis markers. Further characterization of the stem cell-like and metastatic properties of prospectively isolated putative BMIC populations in vitro, and tumour and metastasis formation in vivo will also be undertaken. Additionally, we aim to elucidate the functional role of any novel BMIC markers in self-renewal, tumour formation, and/or metastasis to better determine their potential as therapeutic targets.

Education

2007 — F.R.C.S.(C)  Neurosurgery
2001-2005 — PhD, University of Toronto
1994-1997 — MD, McMaster University
1990-1994 — BSc, Honours Neurobiology, McGill University

Honours and Awards

Year Description
2012 Invited as "Leading Edge Stem Cell Scientist" and table host at 2012 "Renew the World" Canadian Stem Cell Foundation Till and McCulloch Gala
2012 - 2017 Renewal of Tier II Canada Research Chair
2011 - 2014 Terry Fox Foundation - New Investigator Award
2012 CCSRI Innovation Grant
2012 - 2013 OICR Program Project Seed Grant
2011 - 2012 Neurosurgical Research and Education Foundation Young-Clinician Investigator Award
2007 - 2012 Tier II Canada Research Chair, Human Cancer Stem Cell Biology
2007 Fellow of the Royal College of Physicians and Surgeons of Canada
2005 The Royal College of Physicians and Surgeons of Canada Award for Resident Research
2004 Terry Fox Foundation Post MD Fellowship, National Cancer Institute of Canada
2004 American Brain Tumor Association MD-PhD Fellowship
2002 The American Association of Neurological Surgeons/ NREF- American Brain Tumour Association Fellowship

Selected Publications

  • H Zarkoob, SK Singh, SA Mani, M Kohandel. Investigating the link between molecular subclasses of GBM, the epithelial-mesenchymal transition, and CD133+/- cells. PLoS One (in press, April 2013).
  • B Manoranjan, X Wang, R Hallett, C Venugopal, MD Taylor, J Hassell, K Scheinemann, J Provias, S Mak, F Farrokhyar, SE Dunn, SK Singh. FoxG1 interacts with Bmi1 to regulate self-renewal and tumorigenicity of medulloblastoma stem cells. Stem Cells (in press, April 2013).
  • SK Singh, B Manoranjan, C Venugopal. Evolution of barin tumor-initiating cell research: In pursuit of a moving target. Future Neurology 2013; 8(1):1-3.
  • SM Nolte, C Venugopal, N McFarlane, O Morozova, RM Hallett, E O'Farrell, B Manoranjan, NK Murty, E Kachur, P Klurfan, J Provias, JA Hassell, M Marra, SK Singh. A cancer stem cell model for studying brain metastases from primary lung cancer. JNCI, AOP Februry 15, 2013:1-12.
  • C Venugopal, B Manoranjan, N McFarlane, E O’Farrell, S Nolte, X Wang, J Kwiecien, S Wang, M Siu, SK Singh. The GBM secretome induces transformation of human neural precursor cells. Journal of Neuro-oncology 2012 Sep;109(3):457-66.
  • C Lee, Abbas Fotovati, Nichole McFarlane, Chitra Venugopal, Joanna Triscott, Ash Singhal, Christopher Dunham, Maite Verreault, Marcel Bally, Brent Reynolds, Stephen Yip, Hiroaki Wakimoto, Aru Narendran, Sheila K Singh, Sandra E Dunn. Polo-Like Kinase 1 (PLK1) Inhibition Kills Brain Cancer Cells and Suppresses Self- Renewal of Brain Tumour Initiating Cells. Stem Cells. 2012 Jun;30(6):1064-75.
  • C Venugopal, N McFarlane, SM Nolte, B Manoranjan, SK Singh. Processing of primary brain tumor tissue for stem cell assays and flow sorting. Journal of Visual Experimentation (JoVE) 2012 Sep 25;(67).
  • B Manoranjan, C Venugopal, SE Dunn, K Scheinemann, B Doble, SK Singh. Medulloblastoma Stem Cells. CANCER LETTERS. 2012 Jul 14. [Epub ahead of print]
  • B Manoranjan, C Venugopal, N McFarlane, B Doble, SE Dunn, K Scheinemann, SK Singh. Medulloblastoma stem cells: where development and cancer cross pathways. Pediatric Research; 2012 Apr;71(4 Pt 2):516-22.24.
  • C Venugopal, N Li, X Wang, B Manoranjan, M Lenkiewicz, T Gunnarsson, R Hollenberg, P Klurfan, N Murty, C Wynder and SK Singh. Bmi1 marks intermediate precursors during differentiation of human brain tumor initiating cells. Stem Cell Research 2012: 8; pp 141–153.
  • D Reddy, T Gunnarsson, K Scheinemann, JP Provias, SK Singh. Choroid Plexus Papilloma: A rare presentation with a novel surgical approach. Minimally Invasive Neurosurgery 2011; 54: 264-267.
  • D Sommer, W Minet, SK Singh. Endoscopic Transnasal Drainage of Frontal Epidural Abscesses. Journal of Otolaryngology2011: 40(5), pp401-406.
  • A Fotovati, S Abu-Ali, PS Wang, C Lee, JY Chen, S Franciosi, J Triscott, Y Nakamura, Y Sugita, T Uchiumi, M Kuwamo, BR Leavitt, SK Singh, B Reynolds, A Jury, C Jones, CJ Pallen, SE Dunn. YB-1 is a key factor in normal brain development and contributes to gliomagenesis through the maintenance of neural stem cells. Cancer Research 2011: 71(16): 5569-78.
  • Trauma Association of Canada National C-spine Working Group members (lead author Seen Chung, including SK Singh). National Pediatric Cervical Spine Evaluation Pathway: consensus guidelines. Journal of Trauma2011: 70(4); pp 834-42.
  • X Wang, C Venugopal, B Manoranjan, N McFarlane, E O’Farrell, S Nolte, C Hawkins, T Gunnarsson, R Hollenberg, J Kwiecien, and SK Singh. Sonic hedgehog directly regulates Bmi1 in human medulloblastoma brain tumour initiating cells. Oncogene 2011: AOP June 20, pp1-13).
  • K Scheinemann, F Stan, SK Singh. Gliomatosis cerebri: a multifaceted disease. Pediatric Blood and Cancer 2010: 54(6); pp 856-857.
  • I Kurnaz, SK Singh, L Klimaschewski, O Demir. From birth til death: neurogenesis, cell cycle and neurodegeneration. Anatomical Records 2009: 292(12):1953-61.
  • M Lenkiewicz, N Li and SK Singh. Culture and Isolation of Brain Tumor Initiating Cells. Current Protocols in Stem Cell Biology 2009, Chapter 3:Unit3 3.
  • J Pasternak, M Fulford, J Provias, T Gunnarsson, SK Singh. An Unexpected Intracranial Pressure Crisis: Infant Brain Abscess of Unusual Etiology. Childs’ Nervous System, 2009: 25(3); pp 377-81.
  • M Kohandel, SK Singh, S Sivaloganathanan. Characterization of Brain Cancer Stem Cells: A Mathematical Approach. Cell Proliferation, 2009: 42(4); pp 529-40.
  • SK Singh, ID Clarke and PB Dirks. Cancer stem cells and CNS tumours. Neurosurgery Clinics of North America 2007: 18(1): pp31-38.
  • SK Singh, C Hawkins, ID Clarke, J Bayani, J Squire, T Hide, RM Henkelman, MD Cusimano, PB Dirks. Identification of human brain tumour initiating cells. Nature 2004: 7015(432): pp 396-401.
  • SK Singh, ID Clarke, T Hide, PB Dirks. Cancer Stem Cells in Nervous System Tumours. Oncogene 2004: 23; pp7267-7273.
  • SK Singh, ID Clarke, M Terasaki, VE Bonn, C Hawkins, J Squire and PB Dirks: Isolation of a Cancer Stem Cell from Human Brain Tumours. Cancer Research 2003: 63(18): pp 521-528.

[Sheila K. Singh's publications on Pub Med]

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