Chinten James Lim

Associate Professor

Research Classification

Cell Signaling and Cancer
Leukemia
Immunotherapy
Chemotherapy

Research Interests

tumour cell biology
mechanisms of drug resistance
integrin cell adhesion and migration
tumour microenvironment
pediatric oncology

Relevant Degree Programs

 

Research Methodology

cellular biochemistry
single cell imaging
FRET
TIRF
live cell microscopy
Flow cytometry

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Master's students
Doctoral students
Any time / year round

Integrin cell adhesion in chemotherapeutic resistance. Immunogenic cell death. Cardiomyocyte biology. Pediatric oncology.

I support public scholarship, e.g. through the Public Scholars Initiative, and am available to supervise students and Postdocs interested in collaborating with external partners as part of their research.
I support experiential learning experiences, such as internships and work placements, for my graduate students and Postdocs.
I am open to hosting Visiting International Research Students (non-degree, up to 12 months).

Graduate Student Supervision

Doctoral Student Supervision (Jan 2008 - Mar 2019)
Alpha-integrin expression and function modify chemoresistance and immunogenicity of acute lymphoblastic leukemia (2017)

The overall survival rate for pediatric Acute Lymphoblastic Leukemia (ALL) is >85%, achieved mainly via multi-agent chemotherapy. However, therapeutic options remain limited for those experiencing relapse, thus understanding the causes for treatment failures remains an important priority. In this thesis, I investigate the underlying mechanisms that allow leukemic cells to escape chemotherapy. Specifically, I evaluate how integrin-mediated cell adhesion promotes tumor cell survival by increased pro-survival signaling, enhanced resistance to chemotherapeutics, and decreased presentation of immunogenic cell death (ICD) markers. I show that T-lymphoblast adhesion via α4β1-integrin promotes chemoresistance to doxorubicin-induced apoptosis. Expression of α4δ, a tail-truncated α4-integrin with GFFKR as the cytoplasmic motif, promotes chemoresistance in a manner independent of integrin-mediated adhesion. The adhesion-independent chemoresistance is reproduced by expression of Tacδ, a non-integrin transmembrane receptor fused to the cytosolic GFFKR motif. Additionally, the GFFKR motif-mediated chemoresistance is associated with enhanced Akt activation, Ca²⁺ influx, and drug efflux. GFFKR is a conserved motif found in α-integrins and previously shown to interact with calreticulin, a calcium-binding endoplasmic reticulum chaperone protein. I found that α4-calreticulin interaction was enhanced by cell adhesion, while α4δ-calreticulin interaction occurred in an adhesion-independent manner. Since cell surface calreticulin is a pro-phagocytic marker for cells undergoing ICD, the impact of integrin function on surface calreticulin in lymphoblasts treated with ICD-inducing agents was evaluated. Engagement of integrins via adhesion, or expression of the minimal GFFKR motif as α4δ or Tacδ, was sufficient to reduce the levels of surface calreticulin. Furthermore, surface calreticulin was also reduced for cells co-treated with a β1-integrin activating antibody. The resulting integrin-mediated decrease in surface calreticulin significantly reduced engulfment of the target lymphoblasts by macrophages. Calreticulin expression in lymphoblasts was nullified to assess its role in integrin-mediated chemoresistance. Chemosensitivity was partially restored in calreticulin-null Tacδ cells under non-adherent conditions, and in calreticulin-null wildtype cells under adherent conditions. The affect was partly attributed to calreticulin’s role as a regulator of Ca²⁺ influx and drug efflux. Calreticulin was also implicated as a mediator of cytokine-dependent STAT proliferative signaling. This thesis provides evidence for integrin function and cell adhesion as a physiological pro-survival mediator for T-lymphoblasts.

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Master's Student Supervision (2010-2017)
Role of SDF-1/CXCR4 signaling in regulation of PKA activity during cell migration (2014)

Cell migration plays an important role in development and the immune system, and the signaling pathways governing this process are regulated in a spatial and temporal manner. One important signaling molecule is cAMP-dependent Protein Kinase (PKA), which has been shown to be a key regulator of migration. In migrating cells, PKA activity exists in a gradient that is highest at the leading edge, where it phosphorylates proteins that promote migration. Although the functions of PKA in migration have been identified, upstream regulators of PKA-mediated cell migration have yet to be defined. A candidate for regulation of PKA during migration is the chemokine receptor CXCR4, which has been shown to induce cell migration and signal through PKA-phosphorylatable proteins upon ligation with stromal derived factor-1 (SDF-1). I have created a novel CXCR4 deficient Jurkat cell line, JC4, and show that Jurkat cell migration towards SDF-1 is CXCR4-dependent. As well, we show through biochemical studies that the SDF-1/CXCR4 signaling pathway is an upstream regulator of PKA activation in CHO-CXCR4 cells, J774 macrophages, and Jurkat T-cells. Furthermore, the SDF-1/CXCR4 signaling pathway is an upstream regulator of PKA activation in migrating cells. This is supported by the observation that there is a CXCR4-dependent increase in PKA-phosphorylated substrates at the periphery of J774 macrophages and protrusions of Jurkat T-cells upon SDF-1 stimulation. Furthermore, SDF-1/CXCR4 signaling establishes a PKA activity gradient in migrating Jurkat cells that is highest at the leading edge. These studies define a regulatory role for the SDF-1/CXCR4 signaling pathway in promoting PKA-mediated cell migration.

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Steam pre-treatment and leaching for the production of high quality oil palm residue pellets (2014)

It is estimated that about 26 million metric tons of oil palm oil residues are produced annually in Malaysia. The oil palm residues contain high ash content, high alkali metals and low lignin content. Ash and alkali metals lead to slagging in a combustion reactor and fouling of surfaces in convective tubes of heat exchangers. Low lignin content leads to disintegration of pellets during pellet handling and storage. This research thesis investigated the pelletization performance and the ash reduction on Empty Fruit Bunches (EFB) and Palm Kernel Shell (PKS) of oil palm residues by two different pre-treatment processes: steam explosion and water leaching. Steam explosion for increasing binding ability was performed by reacting EFB/PKS with saturated steam ranging from 120 to 220℃ for 5 minutes in a batch reactor. Water leaching for reducing the ash and alkali metals of EFB and PKS was investigated by immersing the samples in water from 25 to 55℃. The immersion time ranged from instantaneous to 240 minutes. Single pellets were made from water treated and steam treated samples. A significant ash reduction from 5.47 to 2.47 % was found for the EFB pellet due to water leaching. A slight reduction of pellet’s porosity and a significant reduction in ash content suggested that water leaching may be used to improve the quality of EFB as a biofuel. On the other hand, pre-treatment processes were not necessary for PKS, considering low binding ability and no ash reduction after pre-treatments. Kinetic models of EFB and PKS leaching were developed. A mass balance of cross flow process was investigated for evaluating the number of stages for a continuous leaching system of EFB and PKS. The techno-economic analysis showed that the additional leaching process costs $25.75 per tonne in a pellet making line.

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The role of interactions between 4N1K and CD47 on integrin activation and integrin-mediated cell adhesion (2014)

Integrins are heterodimeric, cell-surface receptors that play a role in adhesion and chemoresistance. Integrins can be found in one of two states: an inactivated state where integrin-mediated adhesion is not supported, or in an activated state where integrin-mediated adhesion is possible. CD47 is a cell surface receptor that is said to regulate integrin functions by interacting with integrins and regulating their activation state. A thrombospondin C-terminal motif, RFYVVMWK, has been found to be responsible for cell adhesion and was subsequently shown to be specific for CD47. The 10-mer peptide derived from this sequence, 4N1K, has since been used as the prototypic ligand for CD47 and this interaction has been shown to decrease integrin-mediated adhesion and induce cell aggregation and apoptosis. However, the role of the 4N1K/CD47/integrin axis in chemoresistance has not been investigated. My thesis investigated the consequences of CD47 ligation by 4N1K on integrin-mediated functions.I found that the 4N1K peptide induces binding of a variety of antibodies, including non-specific control antibodies, to the surface of cells. In addition, cells that were deficient in CD47 expression were able to bind substrate-immobilized 4N1K as efficiently as their CD47-expressing parental cells. 4N1K was also found to block cell adhesion and induce cell aggregation in a manner that was independent on CD47 expression. These results suggest that 4N1K may produce artifacts in assays that use antibodies as reporters of integrin activation due to its hyper-adhesive nature, resulting in 4N1K binding to a variety of Ig-containing proteins, such as antibodies and cell-surface proteins. In addition, non-specific binding of 4N1K on cell surfaces and homotypic 4N1K interactions appear to be responsible for many of the observed phenotypes on cell adhesion and aggregation, and may explain the reported CD47-independent effects of 4N1K. As such, I propose that the 4N1K peptide not be used as a ligand to assess the role of thrombospondin/ CD47 interactions on cell functions, since the non-specific adherent nature of 4N1K could lead to erroneous interpretations of experimental data.

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Studies on encapsulation of pelletized biomass (2013)

Hygroscopicity and dust generation are among major challenges to the safe and cost effective use of wood pellets. Wood pellets can rot and disintegrate during storage due to the moisture adsorption from humid environment. In British Columbia, pellets are transported by rail from inland manufacturing plants to a shipping port and stored in silos. At the ports, pellets are loaded from the silo on to the ocean vessel for transport to overseas. Loading is stopped during rain because wood pellets disintegrate when they come into contact with water. The lost revenue from loading shutdown during rain can be large. Furthermore, breakage of wood pellets during handling and storage causes dustiness. Dust and fines may cause adverse health effect, fire, and explosion in storage and silos. Encapsulation of wood pellets with a hydrophobic membrane or surface modification can be a good way to increase water repellent capacity of wood pellets, and avoid dust generation. In this research, commercial wood pellets were coated with a wax solution, linseed oil, cellulose acetate, canola oil, etc. The treated pellets were either dipped in water or exposed to humid environment. The results showed that the investigated liquid coatings increased the durability of wood pellets in water. However, the tested liquid coatings did not decrease water vapor adsorption of pellets significantly. Surface treatments with O₂ etching and CF₄ plasma were applied to render wood pellets hydrophobic. It was demonstrated that CF₄ plasma treatment increased water repellency of wood pellets while O₂ etching without CF₄ deposition step made pellets more hydrophilic. Surface modification with O₂ etching combined with CF₄ deposition created the most hydrophobic surface when pellets were dipped in water. However this combined plasma treatment did not decrease water vapor adsorption from humid environment.

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Publications

 
 

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