• Lim, Chinten James

    Titles
    Scientist Level 1, CFRI
    Assistant Professor, Department of Pediatrics, University of British Columbia
    Degrees / Designations
    PhD
    Primary Area of Research
    Childhood Cancer & Blood Research
    Secondary Area(s) of Research
    Phone
    604-875-2000 ext. 4795
    Fax
    Lab Phone
    604-875-2000 ext. 7206
    Assistant
    Brenda Tse
    Assistant Phone
    604-875-2000 ext. 4904
    Mailing Address
    Child & Family Research Institute
    Room 3092, 950 West 28th Avenue
    Vancouver, BC V5Z 4H4
    Affiliate Websites
    Research Areas
    • Integrin dependent cell adhesion and migration
    • Mechanisms of chemotherapeutic resistance
    • Protein interactions and cell signaling
    • Tumour microenvironment
    Summary

    My research is aimed at understanding the molecular mechanisms governing cell adhesion and motility, in particular those involving white blood cell function in normal as well as in pathologic outcomes.

    Circulating white blood cells represent the immune system’s front-line defense against infection. The successful and accurate targeting of white blood cells to inflamed tissues is facilitated by cell adhesion receptor proteins expressed on the surface of these cells. However, aberrant function of these receptor proteins and the cellular signals that regulate them can lead to diseases of the immune system, including leukemia, lymphoma and autoimmunity.

    My laboratory is focused on understanding the differences in cellular signalling between healthy and diseased cells in order to explore and evaluate novel signalling targets for therapeutic intervention in blood diseases. We employ a multi-disciplinary approach that encompasses cell biology, protein biochemistry, molecular biology and immunology.

    Current Projects

    Acute lymphoblastic leukemia (ALL) is the most common of pediatric cancers. ALL is caused by excessive proliferation of immature lymphocytes in the bone marrow, and their eventual dissemination to other organs. Acquired chemoresistance remains a serious limitation to the successful chemotherapeutic treatment of pediatric ALL, accounting for 20 per cent of all relapse. One mechanism contributing to chemoresistance is promotion of cell survival signaling mediated by lymphoblast cell adhesion to integrin ligands found in the bone marrow stromal environment.

    The α4 integrins are cell adhesion receptors highly expressed in lymphocytes and are required for lymphocyte recruitment at inflammatory sites and engraftment in the bone marrow stroma. As such, dysregulated or aberrant α4 integrin function contributes to blood cancers including leukemias and myelomas. In blood cancers, α4-ligand interaction facilitates dissemination of tumor cells or contributes to the development of chemotherapeutic resistance and subsequent tumor relapse. Targeting of the α4-ligand interaction via α4-neutralizing antibodies can be an effective therapeutic strategy; however, complete abrogation of α4 function has led to the potentially fatal progressive multifocal leukoencephalopathy due to suppression of immuno-surveillance. Thus, novel strategies targeting α4 integrin signaling may be preferable to complete α4 blockade.

    The adhesive and signaling function of α4 is mediated via interactions of effector proteins with the α4-cytoplasmic domain (α4-tail). Lymphocyte adhesion to substrate via α4 integrins confers enhanced chemotherapeutic resistance attributable to increased activation of cell survival pathways. We recently characterized a tail-truncated α4 mutant that conferred enhanced chemoresistance in an adhesion-independent manner in T-leukemia cells. The gain of chemoresistance effect does not require the extracellular ligand binding capacities of α4, nor of the contribution of β1 integrin subunit. We are currently characterizing the proteins that interact with the truncated α4-tail, reasoning that the interaction/s may constitute the switch for activating the pro-survival signaling. We are also elucidating the moelcular mechanism responsible for the integrin adhesion-based promotion of chemoresistance. A detailed understanding of these mechanisms will reveal novel molecular targets for their targeting in abrogating cell adhesion mediated chemoresistance.

    We are also attempting to understand the contribution of bone marrow stromal derived signals in activation of lymphocyte integrins, and assessing the outcomes on chemotherapeutic induced apoptosis. In that regard, we are evaluating if integrin activation with and without the accompanying cell adhesion have differential effects on either chemoresistance or drug-induced apoptosis. 

    Selected Publications

    Leclair P, Lim CJ. CD47-Independent Effects Mediated by the TSP-Derived 4N1K Peptide*. PLoS ONE (2014) 9(5): e98358. PMID:24848268   *F1000 Recommended

    Chen H, Mohan P, Jiang J, Nemirovsky O, He D, Fleisch MC, Niederacher D, Pilarski LM, Lim CJ, Maxwell CA. Spatial regulation of Aurora A activity during mitotic spindle assembly requires RHAMM to correctly localize TPX2. Cell Cycle (2014) 13(14):2248-61. PMID:24875404

    Liu CC, Leclair P, Yap SQ, Lim CJ. The Membrane Proximal KxGFFKR Motif of α-Integrin Mediates Chemoresistance*. Molecular and Cellular Biology (2013) 33:4334-45. PMID:24001772  *MCB Spotlighted Article

    Lee HS*, Anekal P*, Lim CJ*, Liu CC, Ginsberg MH. Two modes of integrin activation form a binary molecular switch in adhesion maturation#. Molecular Biology of the Cell (2013) 24:1354-62. PMID:23468527 *equal contribution #ASCB Highlighted

    Sun G, Cheng SY, Chem M, Lim CJ, Pallen CJ. Protein tyrosine phosphatase α phosphotyrosyl-789 binds BCAR3 to position Cas for activation at integrin-mediated focal adhesions. Molecular and Cellular Biology (2012) 32:3776-3789. PMID:22801373 

    Lee HS*, Lim CJ*, Puzon-McLaughlin W, Shattil SJ, Ginsberg MH. RIAM Activates Integrins by Linking Talin to Ras GTPase Membrane-targeting Sequences. Journal of Biological Chemistry (2009) 284:5119-5127. PMID:19098287 *equal contribution

    Lim CJ*, Kain KH*, Tkachenko E, Goldfinger LE, Gutierrez E, Allen MD, Groisman A, Zhang J, Ginsberg MH. Integrin-mediated protein kinase A activation at the leading edge of migrating cells. Molecular Biology of the Cell (2008) 19:4930-41. PMID:18784251*equal contribution

    Lim CJ, Han J, Yousefi N, Ma Y, Amieux PS, McKnight GS, Taylor SS, Ginsberg MH. α4 Integrins are Type I cAMP-dependent protein kinase-anchoring proteins*. Nature Cell Biology (2007) 9:415-421. PMID:17369818   *Featured Article

    Han J, Lim CJ, Watanabe N, Soriani A, Ratnikov B, Calderwood DA, Puzon-McLaughlin W, Lafuente EM, Boussiotis VA, Shattil SJ, Ginsberg MH. Reconstructing and Deconstructing Agonist-induced Activation of Integrin αIIbβ3 (Platelet GPIIb-IIIa)*. Current Biology (2006) 16:1796-1806. PMID:16979556   *Featured Article

    Anthis NJ, Haling JR, Oxley CL, Memo M, Wegener KL, Lim CJ, Ginsberg MH and Campbell ID. Beta integrin tyrosine phosphorylation is a conserved mechanism for regulating talin-induced integrin activation. Journal of Biological Chemistry (2009) 284:36700-36710. PMID:19843520

    Jones, CA, Nishiya N, London NR, Zhu W, Sorensen LK, Chan AC, Lim CJ, Chen H, Zhang Q, Schultz PG, Hayallah AM, Thomas KR, Famulok M, Zhang K, Ginsberg MH and Li DY. Slit2-Robo4 signalling promotes vascular stability by blocking Arf6 activity. Nature Cell Biology (2009) 11:1325-1331. PMID:19855388

    Additional links:         Google Scholar           Research Gate


    Grants
    • Canadian Institutes of Health Research (CIHR) Operating Grant (2014-19)
    • National Sciences and Engineering Research Council (NSERC) – Discovery Grant (2012-17)
    Honours & Awards
    • The Leukemia and Lymphoma Society of Canada (LLSC) OG (2010-2012)
    • CFI/BCKDF – Leaders Opportunity Fund (2010) 
    • The Leukemia and Lymphoma Society (U.S.A.) – Fellow, Career Development Program (2004–07)
    • Canadian Institutes of Health Research (CIHR) – PhD Studentship (1997-2002)
    Research Group Members

    • Pascal Leclair – Research Assistant
    • Chi-Chao Liu (Jack) – PhD candidate 
    • Daniel He – MSc candidate
    • Eric Zhao – MSc candidate (Co-supervisor: Dr Mu Chiao)
    • Sara Alhowar – Directed Studies, Summer Student
    • Alishah Saferali – Volunteer, Summer Student
    • Hui Wang – Visiting Scholar
    Lim Lab Alumni

    Eva Yap (RA), Pascal Leclair (MSc), Melissa Li (RA), Jenny Zhao (SS, V), Lawrence Woo (SS), Joyce Chang (SS), Denny Zheng (V), Steven Luca (V), Linda Wei (HSP)

    Persons interested in joining my laboratory are welcomed to apply by submitting a CV and cover letter indicating scientific interests.