• Integrin dependent cell adhesion and migration
• Mechanisms of chemotherapeutic resistance
• Protein interactions and cell signaling
• Tumour microenvironment

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 frontline 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.

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% 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.

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

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

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

CIHR Operating Grant - PA: Cancer Research 2013

National Sciences and Engineering Research Council (NSERC) – Discovery Grant, 2012-2017

The Leukemia and Lymphoma Society of Canada (LLSC) – Operating Grant, 2010-2012

Canadian Foundation for Innovation (CFI) and British Columbia Knowledge Development Fund (BCKDF) – Leaders Opportunity Fund, 2010

Child & Family Research Institute (CFRI) – Establishment Award, 2009-2012

The Leukemia and Lymphoma Society (U.S.A.) – Fellow, Career Development Program, 2004–2007

Canadian Institutes of Health Research (CIHR) – PhD Studentship, 1997-2002