sheila K. singh, MD PhD FRCSC

Scientist, McMaster Stem Cell and Cancer
Research Institute (SCC-RI)
Assistant Professor, Department of Surgery, Division of Neurosurgery, Faculty of Health Sciences

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 training specializing in pediatric neurosurgery.

Dr. Singh's research program is centred on the study of cancer stem cells. She recently 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.

Her research program will focus on further molecular and genetic characterization of the brain tumour initiating cell (BTIC), and the molecular signalling pathways that are dysregulated in this cell to allow for brain tumorigenesis. This work is articulated in (3) major research aims:

1. Characterization of the Heterogeneity of Human BTICs
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 BTIC activity, Dr. Singh's lab will further define novel candidate cell surface markers to enrich for cancer stem cells. Using fluorescent activated cell sorting for multiple markers and conducting prospective isolation of different classes of brain tumour stem cells and gene expression profiling of tumour stem cells compared to their non-self-renewing neighbours, could potentially lead to the development of a molecular signature for each brain tumour subtype that wil provide the platform to target new chemotherapies.

2. Comparative Analysis of Normal vs Tumorigenic Human Neural Stem Cells expressing CD133
Mechanisms that govern self-renewal and multipotentiality in a normal NSC might be dysregulated to generate a brain tumour. To understand the molecular mechanisms of BTIC self-renewal utilize targeted gene expression profiling of CD133+ and CD133- cells within a brain tumour population to elucidate the key molecular players in BTIC self-renewal, and conduct comparisons of normal NSCs and BTICs to discover the genes that are upregulated during the stages of transformation. Using her xenograft model coupled with either transgenic overexpressing BTICs or siRNA knockdown, Dr. Singh's lab will respectively overexpress or underexpress key molecular mediators in the BTIC population permitting the functional characterization of signalling pathways that are disrupted during the likely transformation of the NSC to a BTIC.

3. Development of Therapeutic Targets for Brain Tumours.
The cancer stem cell hypothesis predicts that even if a tumour shows a substantial decrease in size in response to a therapy, if the cancer stem cells are spared, the tumour will regrow and the patient will have a clinical relapse. Capitalizing on approaches described in Research Aim 1 and 2 above, Dr. Singh will apply rapid prospective purification of the BTIC, using a host of new potential BTIC markers, which may allow clinicians to pinpoint the transformed cell within a lineage hierarchy, and target it with appropriately tailored drug and molecular therapies. A functional analysis of BTICs from individual patients using in vitro clonogenic assays and in vivo tranplantation assays may also provide a novel means for testing of new treatment strategies that focus on the eradication of the tumour-maintaining BTIC.

Education and Certifications
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

Selected Honours and Awards
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 (Declined)
2003 The Hospital for Sick Children Clinician Scientist Training Program Award
2002 Miriam Neveren Memorial Award, University of Toronto
2002 Chisholm Memorial Fellowship, University of Toronto
2002 The American Association of Neurological Surgeons/ NREF- American Brain Tumour Association Fellowship

Publications
SK Singh, C Barlas, P Franks and RK Mishra: A neurochemical basis for the antipsychotic activity of loxapine: Interactions with D1, D2, D4 and 5HT2 receptor subtypes. J Psychiatry Neurosci 1996: 21: pp 29-35.

A Carlotti, D Bohn, SK Singh, D Berry, JT Rutka, ML Halperin: A Method to Estimate Urinary Electrolyte Excretion in Patients at risk for Cerebral Salt Wasting. Journal of Neurosurgery 2001: 95: pp 420-424.

SK Singh, D Berry, ML Halperin, MD Cusimano: Cerebral Salt Wasting: Truths, Fallacies, Theories and Challenges. Critical Care Medicine 2002: 30(11): pp 2575-2579.

SK Singh, L Rickards, J Hurlbert, R Apfelbaum, D Maiman and MG Fehlings: Occipitocervical Reconstruction with the OMI Loop: Results of a multicentre evaluation. Journal of Neurosurgery Spine 2003: 98: pp 239-246.

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.

Report and Citation of above paper (ref 5) in ScienceNews Focus: Mutant Stem Cells may seed Cancer. Science 2003: Marx, J: 301(5638): pp 1308-1310.

Report and Citation of above paper (ref 5) in Nature Reviews Cancer: Applying the principles of stem cell biology to cancer. Nature Reviews Cancer 2003: Pardal R, Clarke MF, Morrison SJ: 3: pp 895-902.

PB Dirks and SK Singh. Cancer Stem Cells. The Lancet 2004

SK Singh, ID Clarke, T Hide, PB Dirks. Cancer Stem Cells in Nervous System Tumours. Oncogene 2004: 23; pp7267-7273.

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.

Report and Citation of above paper (ref 10) in Nature News and Views: At the root of brain cancer. Nature 2004: Clarke, M: 7015(432): pp 281-282.

SK Singh, ID Clarke and PB Dirks. Cancer stem cells and CNS tumours. Neurosurgery Clinics of North America 2007: 18(1): pp31-38.

 

Feature Publications



"Identification of Human Brain
Tumour Initiating Cells"

Singh Lab

Research Technician
Monika Lenkiewicz

Postdoctoral Fellows
Na Li
Chitra Venugopal

Student
Kevin Wang

Medical Secretary,
Department of Surgery
Fidelma DiFlorio

Program Manager
Dawn Lilley

Administrative Assistant
Julie McBride