Research Institute in Oncology and Hematology

Spencer Gibson

Mechanisms of Cell Death in Leukemia and Tumours

Contact:Spencer Gibson
Head of Cell Biology, Research Institute in Oncology and Hematology
Professor (tenured), Departments of Biochemistry and Medical Genetics and Immunology
University of Manitoba
phone: 204-787-2051
Email: Dr Spencer Gibson PhD



Discovering Signal Transduction Pathways Regulating Cell Death

In maintaining integrity and homeostasis of multicellular organisms, the balance between cell death and survival is fundamentally important. When this balance is altered, diseases occur such as cancer. One protein important in the regulation of cell death is the Bcl-2 BH-3 only member BNIP3. BNIP3 expression is induced under low oxygen (hypoxia) conditions and is over expressed in solid tumours in hypoxic regions. When BNIP3 is over expressed in cancer cells it induces cell death mediated by mitochondrial dysfunction. This cell death instead of being apoptotic is autophagic (a new form of programmed cell death). This paradox of BNIP3 killing cancer cells and being over expressed in live cells within tumours is a focus of our research. To date three explanations could account of these differences. The first difference is growth factors block BNIP3 cell death function and tumours have deregulated growth factor signaling leading to cell survival (see below). Secondly, BNIP3 is also localized in the nucleus of tumour cells prevent its interaction with the mitochondria blocking its cell death function. Finally, the BNIP3 gene is mutated to an inactive protein. This protein acts in a dominant negative fashion blocking hypoxia induced cell death. The importance of these mechanisms for cancer progression and treatment is under active investigation.

Cell survival is as important as cell death. The epidermal growth factor receptor (EGFR) is expressed at high levels in several cancers such as breast cancer. We discovered that pretreatment of breast cancer cell lines with epidermal growth factor (EGF) effectively blocked drug and death receptor induced apoptosis. This protection from apoptosis is mediated by a serine threonine kinase called AKT through up-regulation of the Bcl-2 anti-apoptotic family member Mcl-1. Besides breast cancer, we have found that a lipid, lysophosphatic acid (LPA) blocks apoptosis in chronic lymphocytic leukemia (CLL) cells using a similar mechanism. We are currently investigating the regulatory elements controlling Mcl-1 expression.

Molecular-based therapies could alter the balance between cell death and survival towards killing cancer cells. Tumour necrosis factor related apoptosis-inducing ligand (TRAIL) selectively kills cancer cells while normal cells are resistant to TRIAL-induced apoptosis. In collaboration with Dr. James Johnston, we are investigating the potential of TRAIL as a therapy for chronic lymphocytic leukemia (CLL) alone or in combination with chemotherapy.

In addition, we previously discovered that chemotherapeutic drugs increase TRAIL death receptor (DR4/5) expression and this contributes to drug-induced apoptosis. We are defining the regulatory elements controlling DR4/5 expression in CLL cells to enhance the clinical effectiveness of TRAIL.

The goal of this research is to define the signal transduction pathways leading to cell death or survival. This will elucidate pharmaceutical targets that could alter the cellular balance in favour of cell death. This research will be the foundation to establish clinical trials using molecular targeted therapies to increase effectiveness of chemotherapy in cancer.

Learn more about Dr Gibson's research with ZAP70

Team Members

  • Elizabeth Henson (Research Associate - Lab Manager)
  • Yongqiang Chen (Research Associate)
  • Ganchimeg Ishdorj (Research Associate - Cluster project manager)
  • Ali Ahmed (PDF)
  • Sudhadip Das (PDF)
  • Miriam Derksen (MSc)
  • Anna Blankstein (MSc)
  • Alexandra Ciapala (MSc)
  • Aaron Chanas-Larue (MSc)
  • Amandeep Singh (MSc)

Active Funding

CIHR

Research operating grant Title: Targeting the regulation of subtypes of autophagy in cell survival and death to develop novel treatment strategies for glioblastoma
Amount: $100,000/yr 2016-2017

Research Manitoba

Manitoba Partnership Program
Title: Roles of macroautophagy (mAutopahgy) and Chaperone-Mediated Autophagy (CMA) in regulating Cell Death under hypoxia in cancer
Amount: $65,000/yr 2015-2016

Leukemia and Lymphoma Society of Canada

Operating Grant
Title: Control of Malignant B cell migration by PI-3 Kinase.
Amount: $60,000/yr 2015-2017
Co-applicant

Leukemia and Lymphoma Society of Canada

Operating Grant
Title: The role of metabolism in ZAP70 expressing CLL cells.
Amount: $60,000/yr 2015-2017

Research Manitoba

Collaborative Research Cluster grant
Title: An Innovative Cancer Research Model: Integrated Multidisciplinary CLL Research Cluster
Amount: $500,000/yr 2015-2020

Canadian Breast Cancer Foundation- Prairie Chapter

Operating Grant
Title: The role of lysosome membrane permeabilization (LMP) in cell death of breast cancer cells
Amount: $125,000/yr 2013-2016

Canadian Cancer Society Research Institute

Operating Grant
Title The role of lysosome membrane permeabilization (LMP) in cell death of chronic lymphocytic leukemia cells
Amount $67,000/yr 2013-2016

NSERC Discovery Grant

Operating grant
Title: Role of BH3 only protein BNIP3 in regulating cell survival in the brain.
Amount: $38,000/yr 2015-2020

CancerCare Manitoba Foundation

Infrastructure Grant
Title: Translational Research Program
Amount: $92,475/yr 2007-2015


Invited Seminars and Presentations at Symposia/Meetings

  1. CLL Advocacy Educational Conference, Niagara Falls
    November, 2008

  2. Title: Understanding how to therapeutically target survival and death pathways in cancer
    Saskatchewan Cancer Agency
    May, 2009

  3. Title: Live and Let Die: How to selectively target cancer cells to die?
    The Arthur and Sonia Labatt Brain Tumour Research Centre, University of Toronto
    June, 2010

  4. Title: Live and Let Die: How to selectively target cancer cells to die?
  5. Department of Biochemistry, Virginia Commonwealth University
    January 2011

  6. Title: Live and Let Die: How to selectively target cancer cells to die?
  7. Department of Microbiology and Immunology, Dalhousie University
    August 2011

  8. Title: Translational Research Overview: Bridge over troubled waters
  9. All India Institute of Medical Sciences (AIIMS)
    Nov. 2011

  10. Title: CLL Research: Canadian perspective
  11. CLL conference, Niagara Falls, ON
    April, 2012

  12. Title: Live and Let Die: How to selectively target cancer cells to die?
    Department of Pediatrics, MD Anderson Cancer Center, Houston, TX
    May, 2012

  13. Title: When survival turns to death, understanding the regulation of reactive oxygen species in autophagy and apoptosis.
    International Symposium on Mechanisms of Cell Death, Malaga Spain
    June 2013

  14. Title: Understanding how to therapeutically target survival and death pathways in cancer
    Department of Physiology, University of Lausanne, Switzerland
    June 2013

  15. Title: Manitoba’s Leader in Cancer Research
    Terry Fox Research Institute Prairie Node Meeting, Saskatoon Saskatchewan
    June 2013

  16. Title: Role of Reactive oxygen species in autophagy
    Signal Transduction Group Annual Retreat, University of Alberta, Edmonton, AB
    May, 2014

  17. Title: To die another Day
    Canadian Oxidative Stress Conference, Ottawa, ON
    June, 2014

  18. Title: To Live or Let Die: Role of hypoxia induced autophagy in cell death.
    Vancouver Autophagy Symposium, BC Cancer Agency, Vancouver, BC
    Sept. 2014

  19. Title: Collaborative Research is Personalized Now!
    Cancer Research Institute of Northern Alberta (CRINA) Retreat, University of Alberta, Edmonton, AB
    January, 2015

  20. Title: The double edge sword of Autophagy
    Department of Biochemistry
    University of Saskatchewan
    Saskatoon, SK, March, 2015

  21. Title: The Canadian Perspective CLL Live: CLL advocacy education conferences
    Niagara Falls, ON, April 2015.

External Service:

1. Reviewer for manuscripts for peer-reviewed scientific journal: Oncogene, Molecular Biology of the Cell, Blood, Cancer, Cancer Research, British Journal of Cancer, Clinical Cancer Research, Molecular Cancer Therapeutics, Molecular Pharmacology, EMBO, BLOOD, Autophagy, Free Radical Biology and Medicine, Cell Death and Differentiation and Carcinogenesis
2. Participated in a teleconference to nominate members of the Cancer A and B grant committees for Canadian Institutes of Health Research
3. Reviewer for grant submitted to the Alberta Innovates for Health Solutions
4. Organizer of Signal Transduction Journal Club Reviewer for manuscripts for peer-reviewed scientific journal
5. External Reviewer for the Saskatchewan Health Research Foundation for Establishment grant, UK Medical Research Council, Swiss Medical Research Funding Agency and Singapore government funding agency.
6. National Institutes of Health BMCT Study Section, Full panel member
7. Special Reviewer P01 grants

Professional Service

  1. Lead, Cell Biology - RIOH
  2. Interim, Provincial Director, Research, CancerCare Manitoba
  3. Director of Translational Research
  4. Scientific Director of the Manitoba CLL Tissue Bank

Publications Since 2010

PubMed Search for Dr Gibson
  1. An LC/MS/MS method for the simultaneous determination of individual sphingolipid species in B cells. Mi S, Zhao YY, Dielschneider RF, Gibson SB, Curtis JM. J Chromatogr B Analyt Technol Biomed Life Sci. 2016 Sep 15;1031:50-60. doi: 10.1016/j.jchromb.2016.07.028. Epub 2016 Jul 16.
  2. Ferroptosis is induced following siramesine and lapatinib treatment of breast cancer cells. Ma S, Henson ES, Chen Y, Gibson SB. Cell Death Dis. 2016 Jul 21;7:e2307. doi: 10.1038/cddis.2016.208.
  3. Tyrosine kinase receptor EGFR regulates the switch in cancer cells between cell survival and cell death induced by autophagy in hypoxia. Chen Y, Henson ES, Xiao W, Huang D, McMillan-Ward EM, Israels SJ, Gibson SB. Autophagy. 2016 Jun 2;12(6):1029-46. doi: 10.1080/15548627.2016.1164357. Epub 2016 May 11.
  4. Bcl-2 family member Mcl-1 expression is reduced under hypoxia by the E3 ligase FBW7 contributing to BNIP3 induced cell death in glioma cells. Chen Y, Henson ES, Xiao W, Shome E, Azad MB, Burton TR, Queau M, Sathya A, Eisenstat DD, Gibson SB. Cancer Biol Ther. 2016 Jun 2;17(6):604-13. doi: 10.1080/15384047.2015.1095399. Epub 2015 Oct 15.
  5. Comparison of outcome of patients with CLL who are referred or nonreferred to a specialized CLL clinic: a Canadian population-based study. Beiggi S, Banerji V, Deneka A, Griffith J, Gibson SB, Johnston JB. Cancer Med. 2016 Jun;5(6):971-9. doi: 10.1002/cam4.559. Epub 2016 Feb 18.
  6. Dielschneider, R.F., Eisenstat, H., Mi, S. Curtis, J.M., Xiao, W., Johnston, J.B., and Gibson SB 2015 Lysomostropic Agents Selectively Target Chronic Lymphocytic Leukemia Cells Due to Altered Sphingolipid Metabolism. Leukemia In press
  7. Li, H., Wu, X., Hou, S., Noh, E., Makondo, K., Du, Q., Wilkins, JA, Johnston, JB, Gibson SB, Lin, F. and Marshall, AJ 2015 Phosphatidylinositol-3,4-biphosphate and its binding protein lamellipodin regulate chemotaxis of malignant B lymphocytes. Journal of Immunology In press
  8. Chen, Y., Henson, E.S., Huang, D. and Gibson SB 2015 Tyrosine kinase receptor EGFR regulates the switch in cancer cells between cell survival and cell death induced by autophagy in hypoxia. Autophagy In press
  9. Chen, Y., Henson, E.S., Xiao, W., Shome, E., Azad, M.B., Burton, T.R., Queau, M., Sathya, A., Eisenstat, D.D., and Gibson SB 2015 Bcl-2 family member Mcl-1 expression is reduced under hypoxia by E3 ligase FBW7 contributing to BNIP3 induced cell death in glioma cells. Cancer Biology Therapy In press
  10. Lafarge ST, Hou S, Pauls SD, Johnston JB, Gibson SB, Marshall AJ. Differential expression and function of CD27 in chronic lymphocytic leukemia cells expressing ZAP-70. Leuk Res. 2015 Jul;39(7):773-8. doi: 10.1016/j.leukres.2015.04.016. Epub 2015 May 2.
  11. Ali JL, Lagasse BJ, Minuk AJ, Love AJ, Moraya AI, Lam L, Arthur G, Gibson SB, Morrison LC, Werbowetski-Ogilvie TE, Fu Y, Nachtigal MW.Differential cellular responses induced by dorsomorphin and LDN-193189 in chemotherapy-sensitive and chemotherapy-resistant human epithelial ovarian cancer cells. Int J Cancer. 2015 Mar 1;136(5):E455-69. doi: 10.1002/ijc.29220. Epub 2014 Sep 26.
  12. Lafarge ST, Li H, Pauls SD, Hou S, Johnston JB, Gibson SB, Marshall AJ. ZAP70 expression directly promotes chronic lymphocytic leukaemia cell adhesion to bone marrow stromal cells. Br J Haematol. 2015 Jan;168(1):139-42. doi: 10.1111/bjh.13063. Epub 2014 Aug 4. No abstract available.
  13. Shi RY, Zhu SH, Li V, Gibson SB, Xu XS, Kong JM. BNIP3 interacting with LC3 triggers excessive mitophagy in delayed neuronal death in stroke.CNS Neurosci Ther. 2014 Dec;20(12):1045-55. doi: 10.1111/cns.12325. Epub 2014 Sep 17.
  14. Lu P, Kamboj A, Gibson SB, Anderson CM. Poly(ADP-ribose) polymerase-1 causes mitochondrial damage and neuron death mediated by Bnip3.J Neurosci. 2014 Nov 26;34(48):15975-87. doi: 10.1523/JNEUROSCI.2499-14.2014.
  15. Dielschneider RF, Xiao W, Yoon JY, Noh E, Banerji V, Li H, Marshall AJ, Johnston JB, Gibson SB. Gefitinib targets ZAP-70-expressing chronic lymphocytic leukemia cells and inhibits B-cell receptor signaling.Cell Death Dis. 2014 Oct 2;5:e1439. doi: 10.1038/cddis.2014.391.
  16. Gehrke I, Bouchard ED, Beiggi S, Poeppl AG, Johnston JB, Gibson SB, Banerji V. On-target effect of FK866, a nicotinamide phosphoribosyl transferase inhibitor, by apoptosis-mediated death in chronic lymphocytic leukemia cells.Clin Cancer Res. 2014 Sep 15;20(18):4861-72. doi: 10.1158/1078-0432.CCR-14-0624. Epub 2014 Aug 29.
  17. Schacter JL, Henson ES, Gibson SB.Estrogen regulation of anti-apoptotic bcl-2 family member mcl-1 expression in breast cancer cells.PLoS One. 2014 Jun 27;9(6):e100364. doi: 10.1371/journal.pone.0100364. eCollection 2014.
  18. Minuk GY, Lerner B, Gibson SB, Johnston JB, Uhanova J, Andonov A, Wu J. Hepatitis B and hepatitis C viral infections in patients with chronic lymphocytic leukemia. Can J Gastroenterol Hepatol. 2014 Mar;28(3):131-4.
  19. Yoon JY, Szwajcer D, Ishdorj G, Benjaminson P, Xiao W, Kumar R, Johnston JB, Gibson SB. Synergistic apoptotic response between valproic acid and fludarabine in chronic lymphocytic leukaemia (CLL) cells involves the lysosomal protease cathepsin B. Blood Cancer J. 2013 Oct 18;3:e153. doi: 10.1038/bcj.2013.50.
  20. Yoon JY, Ishdorj G, Graham BA, Johnston JB, Gibson SB. Valproic acid enhances fludarabine-induced apoptosis mediated by ROS and involving decreased AKT and ATM activation in B-cell-lymphoid neoplastic cells. Apoptosis. 2014 Jan;19(1):191-200. doi: 10.1007/s10495-013-0906-7.
  21. Lafarge ST, Johnston JB, Gibson SB, Marshall AJ. Adhesion of ZAP-70+ chronic lymphocytic leukemia cells to stromal cells is enhanced by cytokines and blocked by inhibitors of the PI3-kinase pathway.Leuk Res. 2014 Jan;38(1):109-15. doi: 10.1016/j.leukres.2013.08.001. Epub 2013 Aug 9.
  22. Beiggi S, Johnston JB, Seftel MD, Pitz MW, Kumar R, Banerji V, J Griffith E, Gibson SB.Increased risk of second malignancies in chronic lymphocytic leukaemia patients as compared with follicular lymphoma patients: a Canadian population-based study. Br J Cancer. 2013 Jul 16. doi: 10.1038/bjc.2013.381. [Epub ahead of print]
  23. Gibson SB. Investigating the role of reactive oxygen species in regulating autophagy. Methods Enzymol. 2013;528:217-35. doi: 10.1016/B978-0-12-****************.
  24. Kriangkum J, Motz SN, Debes Marun CS, Lafarge ST, Gibson SB, Venner CP, Johnston JB, Belch AR, Pilarski LM. Frequent occurrence of highly expanded but unrelated B-cell clones in patients with multiple myeloma. PLoS One. 2013 May 28;8(5):e64927. doi: 10.1371/journal.pone.0064927. Print 2013.
  25. Burton, T. R., Henson, E.S., Azad, M.B., Brown, M., Eisenstat, D.D. and Gibson, S.B. 2013 BNIP3 acts as transcriptional repressor of Death Receptor 5 (DR5) expression and prevents TRAIL induced cell death in gliomas. Cell Death and Disease 4:e587
  26. Li L, Chen Y, Gibson SB Starvation-induced autophagy is regulated by mitochondrial reactive oxygen species leading to AMPK activation 2013 Cell Signal. Jan; 25(1):50-65
  27. Klionsky DJ, Abdall FC et al Guidelines for the use and interpretation of assay for monitoring autophagy 2012 Autophagy Apr; 8(4):445-544
  28. Gibson SB Autophagy in clear cell ovarian cancer, a potential marker for hypoxia and poor prognosis? 2012 J Pathol Sept 6
  29. Banerji, V., and Gibson S.B. 2012 Targeting Metabolism and Autophagy in the Context of Haematologic Malignancies. International Journal of Cell Biology, 2012; 2012:595976 Epub 2012 Jul 8
  30. Yoon JY, Lafarge S, Dawe D, Lakhi S, Kumar R, Morales C, Marshall A, Gibson SB, Johnston JB Association of interleukin-6 and interleukin-8 with poor prognosis in elderly patients with chronic lymphocytic leukemia 2012 Leuk Lymphoma Sep; 53(9):1735-42.
  31. Ishdorj, G., Li, L. and Gibson S.B. 2011 Regulation of autophagy in hematological malignancies: role of ROS. Leuk Lymphoma. 2012 Jan;53(1):26-33
  32. Li, L. and Gibson SB. 2011 Reactive oxygen species regulate autophagy during cancer: implication for cancer treatment Free Radic Biol Med. 2012 Oct 1; 53(7); 1399-410.
  33. Ishdorj, G, Johnston, JB, and Gibson SB. 2011 Cucurbitacin I (JSI-124) activates the JNK/c-jun signaling pathway independent of apoptosis and cell cycle arrest in B Leukemia Cells BMC Cancer 11:268
  34. Yoon, J-Y, Lafarge, S, Dawe, D., Lakhi, S., Kumar, R., Marshall, A, Gibson, S.B. and Johnston, J.B. 2011 Increased Levels of the Age-Related Cytokines are Important Prognostic Markers in the Elderly with Chronic Lymphocytic Leukemia. Leuk Lymphoma. 2012 Apr 4. [Epub ahead of print]
  35. Xiao, W, Sun, J, Johnston, JB and Gibson SB 2011 Death receptor 4 is preferentially recruited to lipid rafts in Chronic Lymphocytic Leukemia (CLL) cells leading to apoptosis. Lymphoma and Leukemia 52:1290-301 Editors Pick, Commentary 52: 1176-1177
  36. Chen, CI, Bergsagel, L., Paul, H., Xu, W., Lau, A., Dave, N., Kukreti, V., Wei, E., Li, HE, Leung Hagenstijn, C., Brandwein, J., Pantoja, M., Johnston, J., Gibson, S., Hernandez, T., Spaner, D., and Trudel, S. 2011 Single agent lenalidomide in the treatment of previously untreated chronic lymphocytic leukemia. Journal of Clinical Oncology 29:1175-81
  37. Myskiw, C., Arsenio, J., Booy, EP, Hammet, C, Deschambault, Y, Gibson, S. B., Cao, J. 2011 RNA species generated during Vaccinia Virus replication are pathogen-associated molecular patterns activating PKR and MDA5 dependant interferon induction and PKR dependant apoptosis. Journal of Virology 413:183-93
  38. Booy EP, Henson EP and Gibson S. B. 2011 Epidermal growth factor regulates Mcl-1 expression through the MAPK-Elk-1 signalling pathway contributing to cell survival in breast cancer. Oncogene. 30:2367-78
  39. Bristow, N, Burton, TR, Henson, ES, Brown, M. and Gibson, S.B. 2011 Truncated forms of BNIP3 act as dominant negatives inhibiting hypoxia-induced cell death. Biochim Biophys Acta.: Mechanism of Disease 1812:302-11
  40. Azad MB, and Gibson S.B. 2010 BNIP3 in Proliferation & Hypoxia-Induced Autophagy NY Acad Sci 1210(1):8-16
  41. Gibson S.B. 2010 A matter of balance between life and death: Targeting reactive oxygen species (ROS)-induced autophagy for cancer therapy. Autophagy 6:835-7.
  42. Ishdorj, G, Johnston, JB, and Gibson SB. 2010 Inhibition of constitutive activation of STAT3 by curcurbitacin-I (JSI-124) sensitized human B- leukemia cells to apoptosis. Mol Cancer Ther. 9:3302-14.
  43. Costantini, JL, Cheung, SMS, Hou, S., Johnson, JB, Wilkins, JA, Gibson, SB and Marshall, AJ 2009 The phosphoinositide-binding adaptor TAPP2 associates with syntrophin and utrophin in B lymphoma and B-CLL cells and functions in cell adhesion. Blood 114:4703-12.
  44. Chen, Y., Azad, M., and Gibson S.B. (2010) Methods for detecting autophagy and for determining autophagy induced cell death. Can J Physiol Pharmacol. 88:285-95



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