Overview

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.

Publications

CD47-ligation induced cell death in T-acute lymphoblastic leukemia
Cell Death & Disease
Pascal Leclair and Chi-Chao Liu and Mahdis Monajemi and Gregor S. Reid and Laura M. Sly and Chinten James Lim
DOI: 10.1038/s41419-018-0601-2
05/2018

Switching Cyclic Nucleotide-Selective Activation of Cyclic Adenosine Monophosphate-Dependent Protein Kinase Holoenzyme Reveals Distinct Roles of Tandem Cyclic Nucleotide-Binding Domains
ACS Chemical Biology
Daniel He and Robin Lorenz and Choel Kim and Friedrich W. Herberg and Chinten James Lim
DOI: 10.1021/acschembio.7b00732
12/2017

a-Integrin expression and function modulates presentation of cell surface calreticulin
Cell Death Dis
Liu, C. C. and Leclair, P. and Monajemi, M. and Sly, L. M. and Reid, G. S. and Lim, C. J.
DOI: 10.1038/cddis.2016.176
2016

CD47-Independent Effects Mediated by the TSP-Derived 4N1K Peptide.
PloS one
Leclair, Pascal and Lim, Chinten James
DOI: 10.1371/journal.pone.0098358
2014

The Membrane Proximal KxGFFKR Motif of a-Integrin Mediates Chemoresistance
Mol Cell Biol
Liu, C. C. and Leclair, P. and Yap, S. Q. and Lim, C. J.
DOI: 10.1128/MCB.00580-13
2013

Two modes of integrin activation form a binary molecular switch in adhesion maturation
Molecular Biology of the Cell
Lee, H.-S. and Anekal, P. and Lim, C.J. and Liu, C.-C. and Ginsberg, M.H.
DOI: 10.1091/mbc.E12-09-0695
2013

Janus films with stretchable and waterproof properties for wound care and drug delivery applications
RSC Adv.
Ethan Lee and Hongbin Zhang and John K. Jackson and Chinten James Lim and Mu Chiao
DOI: 10.1039/c6ra16232k
2016

RIAM Activates Integrins by Linking Talin to Ras GTPase Membrane-targeting Sequences
Journal of Biological Chemistry
Lee, Ho-Sup and Lim, Chinten James and Puzon-McLaughlin, Wilma and Shattil, Sanford J. and Ginsberg, Mark H.
DOI: 10.1074/jbc.M807117200
2009

Integrin-mediated Protein Kinase A Activation at the Leading Edge of Migrating Cells
Molecular Biology of the Cell
Lim, Chinten J. and Kain, Kristin H. and Tkachenko, Eugene and Goldfinger, Lawrence E. and Gutierrez, Edgar and Allen, Michael D. and Groisman, Alex and Zhang, Jin and Ginsberg, Mark H.
DOI: 10.1091/mbc.E08-06-0564
2008

a4 Integrins are Type I cAMP-dependent protein kinase-anchoring proteins
Nature Cell Biology
Lim, C.J. and Han, J. and Yousefi, N. and Ma, Y. and Amieux, P.S. and McKnight, G.S. and Taylor, S.S. and Ginsberg, M.H.
DOI: 10.1038/ncb1561
2007

Reactive oxygen species stress increases accumulation of tyrosyl-DNA phsosphodiesterase 1 within mitochondria
Scientific Reports
Hok Khim Fam and Kunho Choi and Lauren Fougner and Chinten James Lim and Cornelius F. Boerkoel
DOI: 10.1038/s41598-018-22547-8
12/2018

Combination therapy with proteasome inhibitors and TLR agonists enhances tumour cell death and IL-1ß production
Cell Death & Disease
Anthony C Tang and Seyed M Rahavi and Shan-Yu Fung and Henry Y Lu and Hong Yang and Chinten J Lim and Gregor S Reid and Stuart E Turvey
DOI: 10.1038/s41419-017-0194-1
02/2018

A magnetically actuated cellular strain assessment tool for quantitative analysis of strain induced cellular reorientation and actin alignment
Rev. Sci. Instrum.
F. Khademolhosseini and C.-C. Liu and C. J. Lim and M. Chiao
DOI: 10.1063/1.4960567
08/2016

Janus films with stretchable and waterproof properties for wound care and drug delivery applications
RSC Advances
Ethan Lee and Hongbin Zhang and John K. Jackson and Chinten James Lim and Mu Chiao
DOI: 10.1039/C6RA16232K
2016

Magnetically actuated microstructured surfaces can actively modify cell migration behaviour
Biomedical microdevices
Khademolhosseini, F. and Liu, C.-C. and Lim, C.J. and Chiao, M.
DOI: 10.1007/s10544-016-0033-7
2016

Application of periodic loads on cells from magnetic micropillar arrays impedes cellular migration
2015 28th IEEE International Conference on Micro Electro Mechanical Systems (MEMS)
Farzad Khademolhosseini and Chi-Chao Liu and Chinten J. Lim and Mu Chiao
DOI: 10.1109/memsys.2015.7051033
01/2015

Rational design of a PKA-based sensor for cGMP
BMC Pharmacology and Toxicology
Robin Lorenz and Daniel He and Choel Kim and Chinten J Lim and Friedrich W Herberg
DOI: 10.1186/2050-6511-16-s1-a64
2015

Application of periodic loads on cells from magnetic micropillar arrays impedes cellular migration
Proceedings of the IEEE International Conference on Micro Electro Mechanical Systems (MEMS)
Khademolhosseini, F. and Liu, C.-C. and Lim, C.J. and Chiao, M.
DOI: 10.1109/MEMSYS.2015.7051033
2015

Arginase activity in alternatively activated macrophages protects PI3Kp110 delta deficient mice from dextran sodium sulfate induced intestinal inflammation
European Journal of Immunology
Weisser, Shelley B. and Kozicky, Lisa K. and Brugger, Hayley K. and Ngoh, Eyler N. and Cheung, Bonnie and Jen, Roger and Menzies, Susan C. and Samarakoon, Asanga and Murray, Peter J. and Lim, C. James and Johnson, Pauline and Boucher, Jean-Luc and van Rooijen, Nico and Sly, Laura M.
DOI: 10.1002/eji.201343981
2014

Spatial regulation of Aurora A activity during mitotic spindle assembly requires RHAMM to correctly localize TPX2
Cell Cycle
Chen, H. and Mohan, P. and Jiang, J. and Nemirovsky, O. and He, D. and Fleisch, M.C. and Niederacher, D. and Pilarski, L.M. and Lim, C.J. and Maxwell, C.A.
DOI: 10.4161/cc.29270
2014

Protein Tyrosine Phosphatase alpha Phosphotyrosyl-789 Binds BCAR3 To Position Cas for Activation at Integrin-Mediated Focal Adhesions
Molecular and Cellular Biology
Sun, Guobin and Cheng, Suzanne Y. S. and Chen, Min and Lim, Chinten James and Pallen, Catherine J.
DOI: 10.1128/MCB.00214-12
2012

The Conserved Kxgffkr Motif of alpha-Integrin Cytoplasmic Tail Mediates Chemoresistance to Doxorubicin in T-Cell Leukemia
Blood
Liu, Chi-Chao and Leclair, Pascal and He, Daniel and Yap, Eva and Lim, Chinten James
2012

beta Integrin Tyrosine Phosphorylation Is a Conserved Mechanism for Regulating Talin-induced Integrin Activation
Journal of Biological Chemistry
Anthis, Nicholas J. and Haling, Jacob R. and Oxley, Camilla L. and Memo, Massimiliano and Wegener, Kate L. and Lim, Chinten J. and Ginsberg, Mark H. and Campbell, Iain D.
DOI: 10.1074/jbc.M109.061275
2009

Slit2-Robo4 signalling promotes vascular stability by blocking Arf6 activity
Nature Cell Biology
Jones, C.A. and Nishiya, N. and London, N.R. and Zhu, W. and Sorensen, L.K. and Chan, A.C. and Lim, C.J. and Chen, H. and Zhang, Q. and Schultz, P.G. and Hayallah, A.M. and Thomas, K.R. and Famulok, M. and Zhang, K. and Ginsberg, M.H. and Li, D.Y.
DOI: 10.1038/ncb1976
2009

Reconstructing and deconstructing agonist-induced activation of integrin alpha IIb beta 3
Current Biology
Han, Jaewon and Lim, Chinten James and Watanabe, Naohide and Soriani, Alessandra and Ratnikov, Boris and Calderwood, David A. and Puzon-McLaughlin, Wilma and Lafuente, Esther M. and Boussiotis, Vassiliki A. and Shattil, Sanford J. and Ginsberg, Mark H.
DOI: 10.1016/j.cub.2006.08.035
2006

On the yellow brick road to platelet GP IIb-IIIa (Integrin alpha IIb beta 3) activation.
Blood
Watanabe, Naohide and Han, Jaewon and Lim, C. James and Soriani, Alessandra and Puzon-McLaughlin, Wilma and LaFuente, Esther M. and Boussiotis, Vassiliki A. and Ginsberg, Mark H. and Shattil, Sanford J.
2006

Loss of the Dictyostelium RasC protein alters vegetative cell size, motility and endocytosis
Experimental Cell Research
Lim, CJ and Zawadzki, KA and Khosla, M and Secko, DM and Spiegelman, GB and Weeks, G
DOI: 10.1016/j.yexcr.2005.02.002
2005

Assignment of sockeye salmon (Oncorhynchus nerka) to spawning sites using DNA markers
Marine Biotechnology
Corley-Smith, G.E. and Wennerberg, L. and Schembri, J.A. and Lim, C.J. and Cooper, K.L. and Brandhorst, B.P.
DOI: 10.1007/s10126-004-4065-z
2005

RasC plays a role in transduction of temporal gradient information in the Cyclic-AMP wave of Dictyostelium discoideum
Eukaryotic Cell
Wessels, D and Brincks, R and Kuhl, S and Stepanovic, V and Daniels, KJ and Weeks, G and Lim, CJ and Spiegelman, G and Fuller, D and Iranfar, N and Loomis, WF and Soll, DR
DOI: 10.1128/EC.3.3.646-662.2004
2004

Chemoattractant-induced Ras activation during Dictyostelium aggregation
EMBO Reports
Kae, H. and Lim, C.J. and Spiegelman, G.B. and Weeks, G.
DOI: 10.1038/sj.embor.7400151
2004

Cytoskeletal regulation by Dictyostelium Ras subfamily proteins
Journal of Muscle Research and Cell Motility
Lim, C.J. and Spiegelman, G.B. and Weeks, G.
DOI: 10.1023/A:1024471527153
2002

RasC is required for optimal activation of adenylyl cyclase and Akt/PKB during aggregation
Embo Journal
Lim, CJ and Spiegelman, GB and Weeks, G
DOI: 10.1093/emboj/20.16.4490
2001

Efficient detection of DNA polymorphisms by fluorescent RAPD analysis
Biotechniques
CorleySmith, GE and Lim, CJ and Kalmar, GB and Brandhorst, BP
1997

Efficient detection of DNA polymorphisms by fluorescent RAPD analysis
BioTechniques
Corley-Smith, G.E. and Lim, C.J. and Kalmar, G.B. and Brandhorst, B.P.
1997

Production of androgenetic zebrafish (Danio rerio)
Genetics
CorleySmith, GE and Lim, CTJ and Brandhorst, BP
1996

Production of androgenetic zebrafish (Danio rerio)
Genetics
Corley-Smith, G.E. and Lim, C.J. and Brandhorst, B.P.
1996

a-Integrin expression and function modulates presentation of cell surface calreticulin
Cell Death and Disease

Tailoring the homing capacity of human Tregs for directed migration to sites of Th1-inflammation or intestinal regions.
PubMed: 29766641

Tailoring the homing capacity of human Tregs for directed migration to sites of Th1-inflammation or intestinal regions
American Journal of Transplantation

Research

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 a4 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 a4 integrin function contributes to blood cancers including leukemias and myelomas. In blood cancers, a4-ligand interaction facilitates dissemination of tumor cells or contributes to the development of chemotherapeutic resistance and subsequent tumor relapse. Targeting of the a4-ligand interaction via a4-neutralizing antibodies can be an effective therapeutic strategy; however, complete abrogation of a4 function has led to the potentially fatal progressive multifocal leukoencephalopathy due to suppression of immuno-surveillance. Thus, novel strategies targeting a4 integrin signaling may be preferable to complete a4 blockade.

The adhesive and signaling function of a4 is mediated via interactions of effector proteins with the a4-cytoplasmic domain (a4-tail). Lymphocyte adhesion to substrate via a4 integrins confers enhanced chemotherapeutic resistance attributable to increased activation of cell survival pathways. We recently characterized a tail-truncated a4 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 a4, nor of the contribution of ß1 integrin subunit. We are currently characterizing the proteins that interact with the truncated a4-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.

Grants

Canadian Institutes of Health Research (CIHR) Operating Grant (2014-19)

National Sciences and Engineering Research Council (NSERC) – Discovery Grant (2012-17)

The Lim laboratory is a member of the Michael Cuccione Childhood Cancer Research Program of BC Children's Hospital

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)

Research Group Members

Pascal Leclair, Research Technician
Ling Li, Graduate Student
Chi-Chao (Jack) Liu, Postdoctoral Fellow
Foujan Pedari, Graduate student
S.M Reza Rahavi, Doctoral Student
Lakshana Sreenivasan, PhD Student
Anthony Tam, Postdoctoral Fellow
Chau Truong, Graduate Student
Brenda Tse, Research Coordinator