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Sheela A. Abraham PhD
 Sheela A. Abraham
Position(s)
Principal Investigator (CBG Division)
Assistant Professor
Contact Info
613-533-2975

Faculty Bio

Academic Experience

  • Post Doctoral Senior Research Associate, Institute of Cancer Sciences, University of Glasgow, UK (2009-2016)
  • NSERC Post Doctoral Research Fellow, Department of Medicine, University of Cambridge, UK (2004-2008)
  • Ph.D. Department of Pathology and Laboratory Medicine, University of British Columbia, Canada
  • B.Sc. Microbiology, University of Alberta, Canada

Funding

2014-2015   Medical Research Council (UK) Clinical assessment of transcription factor targeting CML
2014-2015   Constellation Pharmaceutics Research Grant
2014-2015   Roche Research Grant
2013-2016   Bloodwise Project Grant (UK) Dual targeting of p53 and c-Myc to eradicate CML stem cells
2012            Elimination of Leukaemia Fund Grant
2012            British Society for Haematology Start-Up Grant

Profile

I obtained my Ph.D. from the University of British Columbia under the supervision of Professor Marcel Bally, developing lipid membrane nanoparticle delivery systems which founded my interest in cancer therapeutics, lipid bilayer chemistry and nano-based structures. My Ph.D. thesis and first 1st authored publication served as the basis of my inventorship toward the development of the FDA approved (2017) liposomal formulation VyxeosTM. Completed clinical trials demonstrate that VyxeosTM treatment doubles the overall median survival rate and reduces the risk of death by 31% for patients with acute myeloid leukaemia (AML). AML, the most common of all adult leukaemias, has the poorest survival rates with pharmacological treatment remaining unchanged for 30 years. After my Ph.D., I carried out a doctoral fellowship in cellular biology supported by the Natural Science and Engineering Research Council (NSERC) with Professor Paul Lehner at the University of Cambridge studying RING ubiquitin E3 ligases that regulate immune receptors. I completed a second post doctorate with Professor Tessa Holyoake, funded by Bloodwise that involved investigating critical pathways in chronic myeloid leukaemia (CML). This study was the first comparative proteomic screen of normal vs CML stem cells with the identification of a therapeutic regimen based on in silico analyses. Our strategy targeting multi-connected nodes based on network analyses proved superior to treatment with the most successful rationally-designed drug of the last century: Imatinib.

Research Programme Focus

Our research involves interrogating signalling events critical to the development and maintenance of both normal haematopoietic and cancer stem cells. To accomplish this, our research integrates biochemical and molecular biological techniques, primary human tissue culturing techniques, nanoparticle characterization and sizing, chromatography, mass spectrometry (MS), RNA sequencing (RNAseq) microscopy, flow cytometry, bioinformatics and network analyses.

Research Interests:

Haematopoietic stem cells are critical in the replenishment and health of blood thus faults in the maintenance of these cells form the basis of haematopoietic malignancies. Haematopoietic stem cells depend on both intra and extracellular signalling events that take place within the bone marrow microenvironment. Evidence indicates that extracellular vesicles (EVs) provide a key role in cell-to-cell communication. Cells produce EVs (or nanoparticles) that can be either endosomally derived vesicles (30-120 nm) or directly formed from the plasma membrane (100 nm-1 µm), and can contain nucleic acids and proteins. The biogenesis of EVs has been observed in unicellular organisms to mammals, thus suggesting an evolutionarily conserved mechanism of cellular communication.

Ongoing Projects:

1)   Understanding leukaemia using biology and bioinformatic-based techniques with the ultimate goal of developing better therapies and detection methods

Chronic myeloid leukaemia (CML) is a clonal disorder, initiated by the expression of the BCR-ABL1 oncogene in cancer stem cells. Most CML patients must take Tyrosine kinase inhibitors (TKIs), such as imatinib mesylate indefinitely, thus TKIs represent a life-long treatment without providing true cure. Our group and others have identified that in CML the existing residual disease, resistant to TKIs is comprised of leukaemic stem cells (LSC). To investigate the biology behind this critical tumour-initiating and maintaining subpopulation, we have conducted systems approaches providing deeper insight into CML and importantly, engineered a more fundamental synthetic lethality proving superior to single target approaches (Abraham et al. Nature. 2016 Jun 8;534(7607):341-6.). To complement and further this work, we are currently investigating extracellular factors and signalling events within the tumour milieu that promote malignancy and identifying biomarkers critical to early diagnosis.

2)   Analyse extracellular vesicles (EVs) produced by stem cells over the lifetime of humans, in order to identify if EVs modulate HSC toward key decision-making processes such as self-renewal, differentiation, quiescence or death

Aging can be defined as a time-dependent physiological decline that slowly impairs tissue homeostasis and leads to a block of the regeneration capacity of organs. Nine candidate ‘aging hallmarks’ have been proposed in the literature, in attempts to define the cellular and molecular processes that specifically contribute to aging which include: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intercellular communication.

Interestingly, as both humans and mice age there is an increase in the number of HSC with a concurrent decrease in stem cell self-renewal capacity and reconstitution potential upon transplantation. Based on previous observations, it was also assumed that cell-intrinsic mechanisms predominantly drove the observed increase of aged HSC, however current studies show that HSC are additionally regulated by extrinsic factors outside the cell. We are investigating circulating EVs produced at different life stages of healthy humans to understand global signalling events that affect the maintenance of HSC during adult human development. Understanding the basic biology and functional characterization of circulating EVs will shed light into extracellular processes contributing to aging stem cells.

Publications

Abraham's Lab