Chinten James Lim
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Integrin cell adhesion in chemotherapeutic resistance. Immunogenic cell death. Cardiomyocyte biology. Pediatric oncology.
Graduate Student Supervision
Doctoral Student Supervision (Jan 2008 - Mar 2019)
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.
Master's Student Supervision (2010-2017)
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.
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.
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.
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.
- Integrins and ERp57 Coordinate to Regulate Cell Surface Calreticulin in Immunogenic Cell Death (2019)
Frontiers in Oncology,
- Tailoring the homing capacity of human Tregs for directed migration to sites of Th1‐inflammation or intestinal regions (2019)
American Journal of Transplantation,
- CD47-ligation induced cell death in T-acute lymphoblastic leukemia (2018)
Cell Death & Disease, 9 (5)
- Combination therapy with proteasome inhibitors and TLR agonists enhances tumour cell death and IL-1β production (2018)
Cell Death & Disease, 9 (2)
- Reactive oxygen species stress increases accumulation of tyrosyl-DNA phsosphodiesterase 1 within mitochondria (2018)
Scientific Reports, 8 (1)
- Tumor Variant Identification That Accounts for the Unique Molecular Landscape of Pediatric Malignancies (2018)
JNCI Cancer Spectrum, 2 (4)
- Switching Cyclic Nucleotide-Selective Activation of Cyclic Adenosine Monophosphate-Dependent Protein Kinase Holoenzyme Reveals Distinct Roles of Tandem Cyclic Nucleotide-Binding Domains (2017)
ACS Chemical Biology,
- A magnetically actuated cellular strain assessment tool for quantitative analysis of strain induced cellular reorientation and actin alignment (2016)
Rev. Sci. Instrum., 87 (8), 085004
- Janus films with stretchable and waterproof properties for wound care and drug delivery applications (2016)
RSC Adv., 6 (83), 79900--79909
- Magnetically actuated microstructured surfaces can actively modify cell migration behaviour (2016)
Biomedical Microdevices, 18 (1)
- α-Integrin expression and function modulates presentation of cell surface calreticulin (2016)
Cell Death Dis, 7, e2268
- Application of periodic loads on cells from magnetic micropillar arrays impedes cellular migration (2015)
2015 28th IEEE International Conference on Micro Electro Mechanical Systems (MEMS),
- Rational design of a PKA-based sensor for cGMP (2015)
BMC Pharmacology and Toxicology, 16 (Suppl), A64
- Arginase activity in alternatively activated macrophages protects PI3Kp110 delta deficient mice from dextran sodium sulfate induced intestinal inflammation (2014)
European Journal of Immunology, 44 (11), 3353-3367
- CD47-Independent Effects Mediated by the TSP-Derived 4N1K Peptide. (2014)
PloS one, 9 (5), e98358
- Spatial regulation of Aurora A activity during mitotic spindle assembly requires RHAMM to correctly localize TPX2 (2014)
Cell Cycle, 13 (14), 2248-2261
- The Membrane Proximal KxGFFKR Motif of α-Integrin Mediates Chemoresistance (2013)
Mol Cell Biol,
- Two modes of integrin activation form a binary molecular switch in adhesion maturation. (2013)
Molecular biology of the cell, 24 (9), 1354-62
- Protein Tyrosine Phosphatase alpha Phosphotyrosyl-789 Binds BCAR3 To Position Cas for Activation at Integrin-Mediated Focal Adhesions (2012)
Molecular and Cellular Biology, 32 (18), 3776-3789
- The Conserved Kxgffkr Motif of alpha-Integrin Cytoplasmic Tail Mediates Chemoresistance to Doxorubicin in T-Cell Leukemia (2012)
Blood, 120 (21)
- beta Integrin Tyrosine Phosphorylation Is a Conserved Mechanism for Regulating Talin-induced Integrin Activation (2009)
Journal of Biological Chemistry, 284 (52), 36700-36710
- RIAM Activates Integrins by Linking Talin to Ras GTPase Membrane-targeting Sequences (2009)
Journal of Biological Chemistry, 284 (8), 5119-5127
- Slit2-Robo4 signalling promotes vascular stability by blocking Arf6 activity (2009)
Nature Cell Biology, 11 (11), 1325-U146
- Integrin-mediated Protein Kinase A Activation at the Leading Edge of Migrating Cells (2008)
Molecular Biology of the Cell, 19 (11), 4930-4941
- alpha 4 integrins are Type I cAMP-dependent protein kinase-anchoring proteins (2007)
Nature Cell Biology, 9 (4), 415-U96
- On the yellow brick road to platelet GP IIb-IIIa (Integrin alpha IIb beta 3) activation. (2006)
Blood, 108 (11), 67A
- Reconstructing and deconstructing agonist-induced activation of integrin alpha IIb beta 3 (2006)
Current Biology, 16 (18), 1796-1806
- Assignment of sockeye salmon (Oncorhynchus nerka) to spawning sites using DNA markers (2005)
Marine Biotechnology, 7 (5), 440-448
- Loss of the Dictyostelium RasC protein alters vegetative cell size, motility and endocytosis (2005)
Experimental Cell Research, 306 (1), 47-55
- Chemoattractant-induced Ras activation during Dictyostelium aggregation (2004)
Embo Reports, 5 (6), 602-606
- RasC plays a role in transduction of temporal gradient information in the Cyclic-AMP wave of Dictyostelium discoideum (2004)
Eukaryotic Cell, 3 (3), 646-662
- Cytoskeletal regulation by Dictyostelium Ras subfamily proteins (2002)
Journal of Muscle Research and Cell Motility, 23 (7-8), 729-736
- RasC is required for optimal activation of adenylyl cyclase and Akt/PKB during aggregation (2001)
Embo Journal, 20 (16), 4490-4499
- Efficient detection of DNA polymorphisms by fluorescent RAPD analysis (1997)
Biotechniques, 22 (4), 690-&
- Production of androgenetic zebrafish (Danio rerio) (1996)
Genetics, 142 (4), 1265-1276