Research Institute in Oncology and Hematology

Kirk McManus

Chromosomal Instability


Dr Kirk McManus

Research Institute in Oncology and Hematology
ON6010-675 McDermot Ave
Winnipeg, MB R3E 0V9
(204) 787-2833 (office)
(204) 787-2150 (lab)
Email: Dr Kirk McManus PhD
Visit my lab's website

Genome Instability

Genome instability is widely associated with a variety tumour types including colon, breast, ovarian and various lymphoma. Mutations that cause chromosome instability (CIN) are now widely recognized as predisposing factors that contribute to the etiology of tumourigenesis. One of my main goals is to identify and characterize genes that regulate chromosome stability in humans to generate a candidate list of genes that may be somatically mutated in CIN tumours. I have previously utilized this approach to identify several key genes that are somatically mutated in colorectal carcinomas exhibiting CIN. Interestingly, many of these genes encode proteins that regulate sister chromatid cohesion and knock-down or knock-out of the genes underlies CIN. Because sister chromatid cohesion appears to be a central theme in colon cancer, I hypothesize that this pathway may also be aberrantly affected in other tumour types exhibiting CIN.

Another major focus of my lab is to identify synthetic lethal (SL) interaction partners for the CIN genes identified above. Conceptually, the somatic CIN mutations present in cancer cells represent a genetic distinction from the normal surrounding tissues, that may permit the selective targeting and killing of cancer cells. Accordingly, a major goal of my work is to identify SL genetic interaction networks for those CIN genes identified above. Utilizing cross-species candidate gene approaches I have begun to uncover candidate SL interaction partners and networks that I am beginning to investigate through RNAi-mediated approaches coupled with high content digital imaging microscopy. Once these interactions are confirmed and validated, chemical libraries will be screened to identify small molecule inhibitors of the novel candidate therapeutic targets. Figure 1.

Team Members

Zelda Lichtensztejn
Lab Manager
Lucille Jeusset MSc Student Examining and exploiting histone post-translational modifications and modifiers in cancer.
Laura Thompson
PhD Student Identification of novel chromosome stability genes in humans.
Chloe Lepage Research Assistant
Yasamin Asbaghi MSc Student Evaluating KIF11 as candidate chromosome instability genes.
Nicole Wilkinson - co-supervised with Dr Mowat MSc Student Identifying synthetic lethal interactors of DLC2.

Publications since 2010

PubMed Listed Publications
  1. The Steroid Receptor RNA Activator Protein (SRAP) Controls Cancer Cell Migration/Motility. Yan, Y., Cooper, C., Hamedani, M.K., Guppy, B., Wayne, X., Tsuyuki, D., Zhang, C., Nugent, Z., Blanchard, A., Davie, J.R., McManus KJ, Murphy, L.C., Myal, Y., and Leygue, E. FEBS Letters 2015 (Accepted).
  2. Targeting SOD1 induces synthetic lethal killing in BLM- and CHEK2-deficient colorectal cancer cells. Sajesh BV, McManus KJ.Oncotarget. 2015 Jul 31. [Epub ahead of print]
  3. Characterizing the prevalence of chromosome instability in interval colorectal cancer. Cisyk AL, Penner-Goeke S, Lichtensztejn Z, Nugent Z, Wightman RH, Singh H, McManus KJ. Neoplasia. 2015 Mar;17(3):306-16. doi: 10.1016/j.neo.2015.02.001.
  4. Mitotic accumulation of dimethylated lysine 79 of histone H3 is important for maintaining genome integrity during mitosis in human cells. Guppy BJ, McManus KJ. Genetics. 2015 Feb;199(2):423-33. doi: 10.1534/genetics.114.172874. Epub 2014 Dec 22.
  5. A novel multiplexed, image-based approach to detect phenotypes that underlie chromosome instability in human cells. Thompson LL, McManus KJ. PLoS One. 2015 Apr 20;10(4):e0123200. doi: 10.1371/journal.pone.0123200. eCollection 2015.
  6. Establishing a Biological Profile for Interval Colorectal Cancers.Cisyk AL, Singh H, McManus KJ. Dig Dis Sci. 2014 May 20. [Epub ahead of print]
  7. Regulation of chromatin structure via histone post-translational modification and the link to carcinogenesis.Thompson LL, Guppy BJ, Sawchuk L, Davie JR, McManus KJ Cancer Metastasis Rev. 2013 Dec;32(3-4):363-76. doi: 10.1007/s10555-013-9434-8.
  8. Synthetic lethal targeting of superoxide dismutase 1 selectively kills RAD54B-deficient cells. Sajesh, B.V., Bailey, M.L., Lichtensztejn, Z., Hieter, P., and McManus, K.J.Genetics. 2013 (Accepted).
  9. Sister chromatid defects are associated with chromosome instability in Hodgkin lymphoma cells. Sajesh, B.V., Lichtensztejn, Z., and McManus, K.J. BMC Cancer. 2013;13:391. (In Press)
  10. Synthetic Genetic Targeting of Genome Instability in Cancer. Cancers 2013;5:739-61
  11. Thompson, L.L., Guppy, B.J., Sawchuk, L., Davie, J.R., and McManus, K.J. Regulation of chromatin structure via histone post-translational modification and the link to carcinogenesis. Sajesh, B.V., Guppy, B.J., and McManus, K.J. Cancer Metast Rev. 2013.
  12. Mutational analysis of chromosome instability genes in serous endometrial cancers. Price, J.C., Pollock, L.M., Rudd, M.L., Fogoros, S.K., Mohamed, H., Hanigan, C.L., NISC Comparative Sequencing Program, Zhang, S., Cruz, P., Hansen, N.F., Cherukuri, P.F., McManus, K.J., Godwin, A.K., Sgroi, D.C., Mullikin, J.C., Wolfsberg, T.G., Merino, M.J., Hieter, P., and Bell, D.W. PLoS ONE. 2013;8:e63313.
  13. An evolutionarily conserved synthetic lethal interaction network identifies FEN1 as a broad-spectrum target for anticancer therapeutic development. van Pel, D.M., Barrett, I.J., Shimizu, Y., Sajesh, B.V., Guppy, B.J., Pfeifer, T., McManus, K.J., and Hieter, P. PLoS Genetics. 2013;9:e10003254.
  14. Predisposition to cancer caused by genetic and functional defects of mammalian Atad5. Bell DW, Sikdar N, Lee Y-Y, Price JC, Chatterjee R, Park H-D, Fox J, Ishiai M, Rudd ML, Pollock LM, Fogoros SF, Mohamed H, Hanigan CL, NISC, Zhang S, Cruz P, Renaud G, Hansen NF, Cherukuri PF, Borate B, McManus KJ, Stoepel J, Sipahimalani P, Godwin AK, Sgroi DC, Merino MJ, Elliot G, Elkahloun A, Vinson C, Takata M, Mullikin JC, Wolfsberg TG, Hieter P, Lim D-S, Myung K. PLoS Genetics. 2011;7:e1002245.
  15. Proteasome nuclear activity affects chromosome stability by controlling the turnover of Mms22, a protein important for DNA repair. Ben-Aroya, S., Agmon, N., Yuen K., Kwok, T., McManus, K., Kupiec, M., and Hieter, P. PLoS Genetics. 2010;6:e1000852.

Book Chapters

Sajesh, B.V., Cisyk, A.L., and McManus, K.J. Synthetic Genetic Approaches in Colorectal Cancer: Exploiting and Targeting Genome Instability in Cancer Metastasis and Genome Instability: Mechanisms, Emerging Themes, and Novel Therapeutic Strategies. Chris Maxwell and Cal Roskelly (Eds). Springer International Publishing AG, Cham, Switzerland (2015).


Research Funding

2016 - 2018 Cancer Research Society - Operating Grant
Principal Investigator: Dr Kirk McManus
Co-Investigator : Dr Mike Mowat
Title: Exploring and exploiting SOD1 as a synthetic lethal interactor of TP53 in cancer.
Total Amount: $120,000

2015 – 2017 CancerCare Manitoba Foundation – Operating Grant
Principal Applicant: Dr. Kirk McManus
Title: Examining PARP1 as a Novel Drug Target in RAD54B-deficient Colorectal Cancer Cells.
Total Amount: $120,000

2013 – 2018 Canadian Foundation for Innovation – Infrastructure Operating Funds
Title: Molecular determinants of chromosome instability in cancer: Identification of therapeutic targets.
Total Amount: $48,000
Co-Applicant(s): None

2012 – 2017 Natural Sciences & Engineering Council of Canada – Discovery Grant
Title: Identifying the molecular determinants of chromosome stability in humans.
Total Amount: $140,000
Co-Applicant(s): None

2011 – 2016 Canadian Institutes of Health Research – Operating Grant
Title: Characterizing and targeting diminished RNF20 expression in cancer
Total Amount: $754,050
Co-Applicant(s): None

Awards

Invited Seminars and Presentations at Symposia and Meetings

  1. Synthetic lethal targeting of colorectal cancer cells through SOD1 inhibition. Drug Discovery & Therapy World Congress. Boston, MA, July 2015.
  2. The CINful side of drug target discovery in cancer. Department of Oncology, University of Alberta, Edmonton, AB, June 2015.
  3. Exploiting genome instability for precision based targeting of cancer. Alberta Genome Instability, Cancer & Aging Research Symposium. Calgary, AB, June 2015
  4. A cancer researcher’s perspective on the multi-faceted assays enabled by the Cytation 3. BioTek Instruments, Inc. Saskatoon, SK, June 2015.
  5. Exploring and exploiting chromosome instability through synthetic lethal approaches. Terry Fox Research Institute – Prairie Node Research Symposium. Winnipeg, MB, June 2015.
  6. The multi-faceted assays enabled by the Cytation 3 from a cancer researcher’s perspective. BioTek Instruments, Inc. Winnipeg, MB, March 2015.
  7. Synthetic lethal targeting of TP53 in cancer. Blueline BioScience. Vancouver, BC, November 2014.
  8. Synthetic lethal approaches to target cancer cells. University of Saskatchewan, 2nd Annual Protein Structure, Function and Malfunction Meeting (Keynote speaker). Saskatoon, SK, June 2014.
  9. Developing new approaches to target and kill cancer. University of Winnipeg, Honors Research Day (Keynote Speaker). Winnipeg, MB, March 2014.
  10. Using genetic tools to identify new candidate drug targets in cancer. Pharmacology and Therapeutics, University of Manitoba, January 2014.
  11. International Conference on Cell & Gene Therapy; Cancer Therapeutics. Orlando, Florida, Oct 2013.
  12. Edge of Science Seminar Series in Genetics. Faculty of Medicine, University of Manitoba, Winnipeg, September 2013.
  13. International Conference on Genetic Syndromes & Gene Therapy. San Antonio, Texas, Nov 2012.
  14. Child & Family Research Institute, University of British Columbia, March 2012.
  15. Edge of Science Seminar Series in Epigenetics. Faculty of Medicine, University of Manitoba, Winnipeg, November 2011.
  16. Department of Biochemistry & Medical Genetics. University of Manitoba, November 2011.
  17. Department of Immunology, University of Manitoba, February 2011.
  18. MICB, Annual MICB Retreat, Gimli, Manitoba, September 2010.
  19. MICB, Annual MICB Retreat, Winnipeg, Manitoba, November 2009
  20. Department of Biochemistry and Medical Genetics, University of Manitoba, September 2009
  21. Biology Department, University of Windsor, Windsor, ON, December 2008 MICB, University of Manitoba, June 2008
  22. Department of Experimental Oncology, University of Alberta, April 2008 Department of Medical Genetics, University of Alberta, April 2008
  23. Abcam Conference on Genome Instability, Puerto Vallarta, Mexico, February 2008

Special Awards and Distinctions

2016 The University of Manitoba Graduate Student Association Excellence in Graduate Teaching and Mentorship Award
2014 Ken Hughes Young Investigator Award for Medical Research, Faculty of Health Sciences, College of Medicine
2014 Rh Award for Outstanding Contributions to Scholarship and Research in the Health Sciences, Winnipeg Rh Foundation Inc./University of Manitoba
2010 – 2012 CIHR/Manitoba Health Research Council Regional Partnership Program – New Investigator Salary Award
2006 – 2009 Canadian Institutes of Health Research Post-doctoral Fellowship
2005 – 2008 Michael Smith Foundation for Health Research Post-Doctoral Fellowship

Professional Service since 2008

  • Scientific Officer, Manitoba Research Chair Committee, Manitoba Health Research Council (2013)
  • Member, Manitoba Epigenetics Network - Scientific Advisory Committee (2013 - present)
  • Member, CIHR Canada Graduate Scholarships Master's Award A (2012 - present)
  • Member, CIHR Doctoral Research Awards A (2012 - present)
  • Member, Faculty of Medicine, Internal CIHR College of Reviewers (2012 - present)
  • Member, Grant Review Panel C, Cancer Research Society, 2010-present
  • Member, Genomic Centre for Cancer Research and Diagnosis Users Committee (2010-present)
  • Member, Radiation Protection Committee, University of Manitoba (2010-present)
  • Member, Israels Student Thesis Award Committee, MICB, 2009 and 2010
  • Member, Studentship Review Committee, Manitoba Health Research Council (2010-12)
  • Member (Ad-hoc), Grant Review, Canadian Breast Cancer Foundation (Prairies/NWT Region), 2009
  • Reviewer for BMC Cancer, PLoS One, Molecular Oncology and Proceeding of the National Academy of Sciences (USA)

Community Service

CIHR Cafe Scientifique, Nature and Nurture (not versus): the New Science of Epigenetics , Jan 2013
Invited Speaker (The Road to a Scientific Research Career), Maple Leaf School Science Club Research Day, April 2010
Invited Speaker (The Long Road to a Career in Academia), Department of Biochemistry and Medical Genetics Student Career Development Series, September 2009
Laboratory Tour/Demonstration, Summer Biomedical Youth Camp, August 2009


Awards to Trainees

Laura Thompson (PhD)
  • 2016-2019 Alexander Graham Bell Canadian Graduate Studentship
  • 2015 Human Genetics Endowment Fund Award
  • 2015 Honorable Mention (Manitoba poster competition), Canadian Student Health Research Forum, Winnipeg, Manitoba
  • 2015 CancerCare Manitoba Oral Presentation Award (best graduate student), CancerCare Manitoba Research Day
  • 2015 1st Place Overall (Platform), CancerCare Manitoba Research Day
  • 2014-2016 Manitoba Health Research Council Graduate Studentship
  • 2014 Phyllis J. McAlpine Graduate Fellowship
  • Department of Biochemistry & Medical Genetics - Human Genetics Endowment Fund Award (2013)
  • Manitoba Poster Competition - Honorable Mention (June 2013)
  • CancerCare Manitoba Research Day - Arnold Portigal Award (Best Graduate Student Poster) (May 2013)
  • CancerCare Manitoba Research Day - Poster - 2nd Place Overall (May 2013)
  • Terry Fox Research Institute MSc Studentship (2012-14)
Lucile Jeusset (MSc)
  • 2015 International Graduate Student Entrance Scholarship
  • 2015 – 2016 Rising Star Studentship, Terry Fox Research Institute
  • 2016-2018 Research Manitoba / CancerCare Manitoba Foundation Studentship
Yasamin Asbaghi (MSc(
  • 2015 International Graduate Student Scholarship
  • 2015 2nd Place Overall (Poster), CancerCare Manitoba Research Day
  • 2014 International Graduate Student Entrance Scholarship
Nicole Wilkinson (MSc)
  • 2015 Breast Cancer Society Hope Scholarship
  • 2016 Research Manitoba - University of Manitoba Graduate Student Federation co-ordinated studentship

Previous Trainees

Amy Cisyk (MSc)
  • CancerCare Manitoba Research Day - Poster - 3rd Place Overall (May 2013)
  • Flying Officer George Finkle Memorial Scholarship (May 2012)
Brent Guppy (PhD)
  • 2015 Mindel and Tom Olenick Studentship in Gastrointestinal Diseases
  • 2015 3rd Place Overall (Platform), CancerCare Manitoba Research Day
  • 2014 Life Sciences Association of Manitoba Most Promising Life Sciences Student
  • 2014 University of Manitoba Emerging Leaders
  • 2014 Human Genetics Endowment Fund Graduate Student Award
  • 2013 Right Honourable Don Mazankowski Award in Cancer Research
  • 2013 Canadian Student Health Research Forum National Poster Competition - CIHR Honorable Mention
  • 2013 Manitoba Poster Competition - Dean of Graduate Studies Poster Award
  • 2012-2014 MHRC/CCMF PhD Studentship
  • Canadian Student Health Research Forum National Poster Competition - CIHR Silver Medal (June 2012)
  • Manitoba Poster Competition - Manitoba Medical Service Foundation Poster Award (June 2012)
  • CancerCare Manitoba Research Day - Poster - 3rd Place Overall (May 2012)
  • Detter Hettig Scholarship (April 2012)
  • Canadian Society for Molecular Biosciences Travel Award (March 2012)
  • Faculty of Graduate Studies Travel Award (March 2012)
Erin McAndrew (MSc)
  • 2015 Phyllis J. McAlpine Graduate Fellowship
  • 2015 – 2016 Rising Star Studentship, Terry Fox Research Institute - declined
  • 2015 – 2016 MSc Studentship, Research Manitoba/CancerCare Manitoba Foundation
  • 2015 College of Medicine Poster Award (Manitoba poster competition), Canadian Student Health Research Forum, Winnipeg, Manitoba
  • 2015 Arnold Portigal Poster Award (best graduate student), CancerCare Manitoba Research Day
  • 2015 1st Place Overall (Poster), CancerCare Manitoba Research Day
Babu Sajesh (Post-Doctoral Fellow)
  • CancerCare Manitoba Research Day - Platform presentation - 3rd Place overall (May 2013)
  • MHRC/CCMF PDF Fellowship (2012-13)
  • CancerCare Manitoba Research Day - Honorable Mention (May 2012)
  • MICB Travel Award, Canadian Cancer Research Conference, Toronto, Ontario (Nov 2011)
  • EMBO Travel Award, Vienna, Austria (June 2011)
  • Manitoba Poster Competition - Dean of Medicine PDF Poster Award (June 2011)
  • CancerCare Manitoba Research Day - Poster - 2nd Place PDF (May 2011)
  • CancerCare Manitoba Research Day - Rick Hester Prize (Best PDF Poster) (May 2010)
  • Brittany Kessler - Undergraduate Student Research Award - Summer Student (2013)
  • Laryssa Sawchuk - Undergraduate Student Research Award - Summer Student (2012)
  • Laryssa Sawchuk - Department of Biochemistry & Medical Genetics -Undergraduate Summer Studentship Award (2012 - declined)
  • Allison Baergen - University of Manitoba



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