Abraham | Biomedical and Molecular Sciences | School of Medicine

Sheela Abraham PhD

Position(s)

Associate Professor

Contact Info

sa183@queensu.ca

613-533-2975

Botterell Hall Office A307

https://abrahamstemcells.com/

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.

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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.

Selected Publications

Latif AL, Newcombe A, Gilroy K, Robertson N, Li S, Stewart H, Terradas M, Rishi Delori L, McGarry L, Reid C, Clark W, Campos J, Kirschner K, Lopez J, J Sakamaki, Ryan K, Tait S, Abraham SA, Holyoake TC,. Higgins BX, Huang X, Copland M, Chevassut T, Keeshan K, Adams PD Abolition of BRD4-mediated repression of p53 target genes and stabilization of p53 is the basis of synergistic lethality of BET inhibitors and MDM2 inhibitors in AML Re-submitted to Nature Communications (IF:12.1)
Grenier-Pleau, I, Tyryshkin K, Le TD, Rudan J, Bonneil E, Thibault P, Zeng K, Lässer C, Mallinson D, Lamprou D, Hui J, Postovit LM, Chan EYW, Abraham SA. Blood Extracellular Vesicles From Healthy Individuals Regulate Haematopoietic Stem Cells as Humans Age. Aging Cell Oct 7;e13245 (IF:7.2)
Pellicano F, Park L, Hopcroft LEM, Shah MM, Jackson L, Scott MT, Clarke CJ, Sinclair A, Abraham SA, Hair A, Helgason GV, Aspinall-O'Dea M, Bhatia R, Leone G, Kranc KR, Whetton AD, Holyoake TL. Hsa-mir183/EGR1-mediated regulation of E2F1 is required for CML stem/progenitor cell survival. Blood. 2018 Feb 5. pii: blood-2017-05-783845. (IF: 17.5)

Hopcroft LEM, Abraham SA, Whetton AD, Holyoake TL. Network topology of leukaemic stem cells: identifying and validating a dual hub. Oncoscience. 2017 Feb 24; 4(1-2):3-4. (IF:3.1)

Abraham SA and Holyoake TL. Casting a NETwork instead of shooting magic bullets. Cell Cycle. 2016 Aug 31:1-2. (IF: 3.7)

*Abraham SA, *Hopcroft LE, Carrick E, Dunn K, Williamson AJK, Korfi K, Park LE, Scott MT, Pellicano F, Pierce A, Copland M, Vetrie D, *Whetton AD, *Holyoake TL. Network profiling of primitive chronic myeloid leukaemia cells reveals a selective and targetable dependency on p53 and c-Myc. Nature. 2016 Jun 8. doi: 10.1038/nature18288. (IF: 42.3)

Abraham SA. Biological analysis of human CML stem cells. Invited book chapter. Methods Mol Biol. 2016; 1465:175-85.

Sinclair A, Park L, Shah M, Calaminus S, Hopcroft LEM, Drotar M, Kinstrie R, Guitart A, Dunn K, Abraham SA, Sansom O, Michie AM, Machesky L, Kranc KR, Graham GJ, Pellicano F, Holyoake TL. CXCR2 and CXCL4 regulate survival and self-renewal of hematopoietic stem/progenitor cells. Blood. 2016 Jul 21; 128(3):371-83. doi: 10.1182/blood-2015-08-661785. (IF: 17.5)

*Chen Y, *Peng C, Abraham SA (second author), Shan Y, Guo Z, Desouza N, Cheloni G, Li D, Holyoake TL, Li S. Arachidonate 15-lipoxygenase is required for chronic myeloid leukemia stem cell survival. J Clin Invest. 2014 Sep 2; 124(9):3847-62. (IF: 11.9)

Abraham SA, Hopcroft L, Bhatia R, Koschmieder S, Whetton AD and Holyoake TL. Models to Study Chronic Myeloid Leukaemia Cancer Stem Cells. Book Chapter in: Cancer Stem Cells Wiley Press 2014.
Williamson AJ, Pierce A, Jaworska E, Zhou C, Aspinall-O'Dea M, Lancashire L, Unwin RD, Abraham SA, Walker MJ, Cadecco S, Spooncer E, Holyoake TL, Whetton AD. A specific PTPRC/CD45 phosphorylation event governed by stem cell chemokine CXCL12 regulates primitive hematopoietic cell motility. Mol Cell Proteomics. 2013 Nov; 12(11):3319-29. (IF: 4.8)

Abraham SA, Holyoake TL. Redirecting traffic using the XPO1 police. Blood. 2013 Oct 24; 122(17):2926-8. (IF: 17.5)

Griaud F, Pierce A, Gonzalez Sanchez MB, Scott M, Abraham SA, Holyoake TL, Tran DD, Tamura T, Whetton AD. A pathway from leukemogenic oncogenes and stem cell chemokines to RNA processing via THOC5. Leukemia. 2013 Apr; 27(4):932-40. (IF: 8.7)

Balabanov S, Evans CA, Abraham SA, Pellicano F, Copland M, Walker MJ, Whetton AD, Holyoake TL. Quantitative proteomics analysis of BMS-214662 effects on CD34 positive cells from chronic myeloid leukaemia patients. Proteomics. 2013 Jan; 13(1):153-68. (IF: 3.1)

Gallipoli P, Abraham SA, Holyoake TL. Hurdles toward a cure for CML: the CML stem cell. Hematol Oncol Clin North Am. 2011 Oct; 25(5):951-66. (IF: 3.1)

Viglianti BL, Ponce AM, Michelich CR, Yu D, Abraham SA, Sanders L, Yarmolenko PS, Schroeder T, MacFall JR, Barboriak DP, Colvin OM, Bally MB, Dewhirst MW. Chemodosimetry of in vivo tumor liposomal drug concentration using MRI. Magn Reson Med. 2006 Nov; 56(5):1011-8. (IF: 3.6)

Abraham SA, Waterhouse DN, Mayer LD, Cullis PR, Madden TD, Bally MB. The Liposomal Formulation of Doxorubicin. Methods Enzymol. 2005; 391:71-97. (IF: 1.9)

Chiu GN, Abraham SA, Ickenstein LM, Ng R, Karlsson G, Edwards K, Wasan EK, Bally MB. Encapsulation of doxorubicin into thermosensitive liposomes via complexation with the transition metal manganese. J Control Release. 2005 May 18; 104(2):271-88. (IF: 7.6 )

Viglianti BL, Michelich CR, Abraham SA, Colvin OM, Yarmolenko PS, Schroeder T, MacFall JR, Bally MB, Dewhirst MW. Chemodosimetry of in-vivo tumor liposome/drug concentration using MRI. International Journal of Radiation Oncology Biology Physics 2004 September, Vol 60, 1, S225–S226. (IF: 5.9)

Viglianti BL, Abraham SA, Michelich CR, Yarmolenko PS, MacFall JR, Bally MB, Dewhirst MW. In vivo monitoring of tissue pharmacokinetics of liposome/drug using MRI: illustration of targeted delivery. Magn Reson Med. 2004 Jun; 51(6):1153-62. (IF: 3.6)

Abraham SA, Edwards K, Karlsson G, Hudon N, Mayer LD, Bally MB. An evaluation of transmembrane ion gradient-mediated encapsulation of topotecan within liposomes. J Control Release. 2004 May 18; 96(3):449-61. (IF: 7.6)

Abraham SA, McKenzie C, Masin D, Ng R, Harasym TO, Mayer LD, Bally MB. Co-encapsulation of doxorubicin and vincristine within liposomes through use of metal ion complexation method in combination with ionophore mediated induction of a pH gradient. Clin Cancer Res. 2004 Jan 15; 10(2):728-38. (IF: 10.1)

Abraham SA, Edwards K, Karlsson G, MacIntosh S, Mayer LD, McKenzie C, Bally MB. Formation of transition metal-doxorubicin complexes inside liposomes. Biochim Biophys Acta. 2002 Sep 20; 1565(1):41-54. IF: (3.4)

Dos Santos N, Mayer LD, Abraham SA, Gallagher RC, Cox KA, Tardi PG, Bally MB. Improved retention of idarubicin after intravenous injection. Biochim Biophys Acta. 2002 Apr 12; 1561(2):188-201. (IF: 3.4)

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