PhD in Medical Biochemistry, University of Calgary, Alberta, Canada
supervisor: Dr. David Bazett-Jones
Post-doctoral training at the Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, USA
supervisor: Dr. Tim Yen
ONCOL 570, Directed Reading in Experimental Oncology, course coordinator
ONCOL 520, Tumor Biology, course coordinator
ONCOL 425, Advance Topics in Cancer Research, instructor for Module 3, Mitosis and Aneuploidy in Cancer
Research training is available for undergraduate summer students, undergraduate research project students (398, 399, 498, 499 courses), undergraduate co-op students, graduate students and post-doctoral fellows. Individuals interested in graduate work in Oncology in my laboratory should have a strong background in molecular biology, biochemistry and/or cell biology, since research projects typically involve the use of platform technologies from these disciplines. Funding for students and fellows is available through application to competitive agencies (e.g., Alberta Innovates, CIHR, NSERC, Alberta Cancer Foundation, CRINA) or from operating grants to the Chan research program.
We have three main areas of research: (i) the role(s) of the RZZ complex in mitotic checkpoint regulation and (ii) the role of the mitotic checkpoint in mitotic catastrophe (iii) cell cycle kinases Wee1 and Myt1 synthetic lethality in breast cancer.
(i) The RZZ complex consists of three proteins, Rod, Zw10 and Zwilch. They are kinetochore proteins that recruit the microtubule motor, dynein/dynactin, to kinetochores but were found to be also essential for the mitotic checkpoint. The RZZ complex is essential for the recruitment of the mitotic checkpoint effector Mad2 to kinetochores. The exact mechanism is still unknown. We are using molecular, biochemical and cell biological approaches to study the structure and function of the mitotic checkpoint apparatus in order to understand the underlying mechanism. (ii) Mitotic catastrophe is a cell death phenomenon that has been observed, however, there is not a molecular marker and the mechanism of action is not known. We are following up on the findings that genotoxic treatments of cancer cells often result in checkpoint adaptation and ultimately mitotic catastrophe. We have observed that prolonged mitotic arrest and centromere fragmentation often accompany mitotic catastrophe. We are examining the role of the mitotic checkpoint in this cell death process. (iii) Wee1 and Myt1 are cell cycle kinases that mediate inhibitory Cdk1 phosphorylation. In addition to being important for regulating the G2/M checkpoint, they are also essential for inhibiting Cdk1 activity at the end of mitosis. MK-1775 is a small molecule inhibitor of Wee1 kinase activity and is currently undergoing Phase I/II clinical trial for multiple cancers. We have identified the Myt1 kinase as a resistance factor for MK-1775 in breast cancers. We are examining the mechanism of Myt1 function in mediating MK-1775 resistance.
Microtubule, mitosis, drug, inhibitor, cell cycle, synthetic lethality, drug resistance mechanism
Cody Lewis, PhD student
Joanne Smith, MSc student
Abigail Linares Cruz, MSc student
Kaushiki Roy, visiting PhD student
Famulski J.K.and Chan G.K. 2007. Aurora B kinase-dependent recruitment of hZW10 and hROD to tension-less kinetochores. Current Biology17, 2143–2149.
Famulski J.K., Vos L.J., Sun X.J. and Chan G.K. 2008. Stable hZW10 residency at kinetochores, mediated through hZwint-1 interaction, is essential for mitotic checkpoint function. J. Cell Biology180:507-520.
Famulski J.K., Vos L.J.,Rattner J.B. and G.K. Chan. 2011. Dynein/dynactin-mediated transport of kinetochore components off kinetochores and onto spindle poles induced by Nordihydroguaiaretic acid. PLoS ONE6(1): e16494. doi:10.1371/journal.pone.0016494
Vos L.J., Famulski J.K. and G.K. Chan. 2011. hZwint-1 Bridges the Inner and Outer Kinetochore: Identification of the Kinetochore Localization Domain and the hZw10 Interaction Domain. Biochemical Journal436(1):157-68.
Moudgil K.D., Westcott N., Famulski J.K., Patel K., Macdonald D., Hang H., Chan G.K.T. 2015. A novel role of farnesylation in targeting a mitotic checkpoint protein, human Spindly to kinetochores. J. Cell Biology208(7):881-96. Highlighted in News - In This Issue: Spindly gets a lipid link to kinetochores Ben Short J Cell Biol 2015 208:860.
Lewis C.W., Jin Z., Macdonald D., Wei W., Qian X.J., Choi W.S., He R., Sun X., and Chan G.K. 2017. Prolonged mitotic arrest induced by Wee1 inhibition sensitizes breast cancer cells to paclitaxel. Oncotarget8(43):73705-73722. doi: 10.18632/oncotarget.17848.
Bukhari, A., Lewis C.W., Pearce J., Luong D., Chan G.K. and Gamper A. 2019. Inhibiting Wee1 and ATR kinases produces tumor-selective synthetic lethality and suppresses metastasis. Journal of Clinical Investigation129(3):1329-1344.