Gordon S Duncan

Gordon S Duncan
Treadwell Therapeutics

BSc. Pharmacology and MSc. Medical Biophysics

About

835
Publications
88,272
Reads
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100,213
Citations
Citations since 2017
126 Research Items
29977 Citations
201720182019202020212022202301,0002,0003,0004,0005,000
201720182019202020212022202301,0002,0003,0004,0005,000
201720182019202020212022202301,0002,0003,0004,0005,000
201720182019202020212022202301,0002,0003,0004,0005,000
Additional affiliations
February 2021 - present
Treadwell Therapeutics
Position
  • Principal Investigator
January 2006 - February 2021
University Health Network
Position
  • Technician
January 2003 - December 2012
Ontario Institute for Cancer Research
Education
September 2000 - July 2002
University of Toronto
Field of study
  • Dept. of Medical Biophysics
May 2000 - May 2002
University of Toronto
Field of study
  • Immunology
September 1989 - August 1993
University of East London
Field of study
  • Pharmacology

Publications

Publications (835)
Article
Angioimmunoblastic T cell lymphoma (AITL) is a peripheral T cell lymphoma that originates from T follicular helper (Tfh) cells and exhibits a prominent tumor microenvironment (TME). IDH2 and TET2 mutations co-occur frequently in AITL, but their contribution to tumorigenesis is poorly understood. We developed an AITL mouse model that is driven by Id...
Article
Mutations in IDH1, IDH2, and TET2 are recurrently observed in myeloid neoplasms. IDH1 and IDH2 encode isocitrate dehydrogenase isoforms, which normally catalyze the conversion of isocitrate to α-ketoglutarate (α-KG). Oncogenic IDH1/2 mutations confer neomorphic activity, leading to the production of D-2-hydroxyglutarate (D-2-HG), a potent inhibitor...
Article
Experimental autoimmune encephalomyelitis (EAE) is a mouse model of multiple sclerosis (MS) in which Th17 cells have a crucial but unclear function. Here we show that choline acetyltransferase (ChAT), which synthesizes acetylcholine (ACh), is a critical driver of pathogenicity in EAE. Mice with ChAT-deficient Th17 cells resist disease progression a...
Article
Type I and II interferons (IFNs) stimulate pro-inflammatory programs that are critical for immune activation, but also induce immune-suppressive feedback circuits that impede control of cancer growth. Here, we sought to determine how these opposing programs are differentially induced. We demonstrated that the transcription factor interferon regulat...
Article
Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) are standard first-line treatments for metastatic ER+ breast cancer. However, acquired resistance to CDK4/6i invariably develops, and the molecular phenotypes and exploitable vulnerabilities associated with resistance are not yet fully characterized. We developed a panel of CDK4/6i-resistant...
Article
Full-text available
Background: Recent studies have demonstrated that T cells can induce vasodilation in a choline-acetyltransferase dependent manner, leading to an increase in T cell migration to infected tissues in response to viral infection, but its role in cancer is unclear. Choline acetyltransferase catalyzes the production of acetylcholine from choline and ace...
Article
Background: TTK (also known as Mps1), a dual-specificity serine-threonine kinase, is critical for the spindle assembly checkpoint (SAC), chromosome alignment and error correction in mitosis. Inhibition of TTK causes premature mitotic exit with unattached chromosomes, resulting in chromosomal missegregation, aneuploidy and cell death. CFI-402257 is...
Article
Full-text available
Despite extensive analysis of pRB phosphorylation in vitro, how this modification influences development and homeostasis in vivo is unclear. Here, we show that homozygous Rb∆K4 and Rb∆K7 knock-in mice, in which either four or all seven phosphorylation sites in the C-terminal region of pRb, respectively, have been abolished by Ser/Thr-to-Ala substit...
Article
Full-text available
Resident macrophages orchestrate homeostatic, inflammatory, and reparative activities. It is appreciated that different tissues instruct specialized macrophage functions. However, individual tissues contain heterogeneous subpopulations, and how these subpopulations are related is unclear. We asked whether common transcriptional and functional eleme...
Article
Full-text available
The tumor suppressor PTEN is disrupted in a large proportion of cancers, including in HER2-positive breast cancer, where its loss is associated with resistance to therapy. Upon genotoxic stress, ataxia telangiectasia mutated (ATM) is activated and phosphorylates PTEN on residue 398. To elucidate the physiological role of this molecular event, we ge...
Article
Mutations in the genes encoding isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) are key drivers of diverse cancers, including gliomas and hematological malignancies. IDH mutations cause neomorphic enzymatic activity that results in the production of the oncometabolite 2-hydroxyglutarate (2-HG). In addition to 2-HG’s well-known effects on tumor cells...
Article
The success of checkpoint inhibitors has accelerated the clinical implementation of a vast mosaic of single agents and combination immunotherapies. However, the lack of clinical translation for a number of immunotherapies as monotherapies or in combination with checkpoint inhibitors has clarified that new strategies must be employed to advance the...
Article
Full-text available
Inflammation is a key contributor to atherosclerosis with macrophages playing a pivotal role through the induction of oxidative stress and cytokine/chemokine secretion. DJ1, an anti-oxidant protein, has shown to paradoxically protect against chronic and acute inflammation. However, the role of DJ1 in atherosclerosis remains elusive. To assess the r...
Article
Significance There are controversial data about the protumoral role of pancreatic cancer stroma, and dissecting multiple aspects will help to develop effective tailored therapies. Interleukin-17A (IL17A) has been reported to accelerate pancreatic acinar–ductal metaplasia, be important for maintaining stem-like cancer cells, and recruit immunosuppre...
Article
In order to sustain proficient life-long hematopoiesis, hematopoietic stem cells (HSCs) must possess robust mechanisms to preserve their quiescence and genome integrity. DNA-damaging stress can perturb HSC homeostasis by affecting their survival, self-renewal and differentiation. Ablation of the kinase ATM, a master regulator of the DNA damage resp...
Article
Full-text available
Diffuse midline gliomas (DMGs) are aggressive childhood brain tumors with a dismal prognosis. Most of these tumors carry K27M mutations in histone H3-encoding genes, particularly H3F3A and HIST1H3B. In addition, activating mutations in ACVR1 and PIK3CA co-occur in a subset of DMGs. To understand how these lesions drive the development of DMGs, we g...
Article
Isocitrate dehydrogenase (IDH) mutations are common genetic alterations in myeloid disorders, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Epigenetic changes, including abnormal histone and DNA methylation, have been implicated in the pathogenic build-up of hematopoietic progenitors, but it is still unclear whether and...
Article
Full-text available
Growth of the axial and appendicular skeleton depends on endochondral ossification, which is controlled by tightly regulated cell–cell interactions in the developing growth plates. Previous studies have uncovered an important role of a disintegrin and metalloprotease 17 (ADAM17) in the normal development of the mineralized zone of hypertrophic chon...
Article
Full-text available
Significance Millions of people have been exposed to asbestos and are at increased risk of developing mesothelioma, an aggressive malignancy resistant to current therapies. Here, we elucidate critical steps in asbestos carcinogenesis: asbestos induces the release of high mobility group box 1 that triggers autophagy. Autophagy activation constitutes...
Article
Full-text available
Abstract The proper communication between gut and brain is pivotal for the maintenance of health and, dysregulation of the gut-brain axis can lead to several clinical disorders. In Parkinson’s disease (PD) 85% of all patients experienced constipation many years before showing any signs of motor phenotypes. For differential diagnosis and preventive...
Article
Full-text available
Primary tumor-derived factors act upon normal cells to generate a pre-metastatic niche, which promotes colonization of target organs by disseminated malignant cells. Here we report that tumor-derived factor-induced activation of the p38α kinase in lung fibroblasts plays a critical role in the formation of a pre-metastatic niche in the lungs and sub...
Article
Full-text available
Proper immune system function hinders cancer development, but little is known about whether genetic variants linked to cancer risk alter immune cells. Here, we report 57 cancer risk loci associated with differences in immune and/or stromal cell contents in the corresponding tissue. Predicted target genes show expression and regulatory associations...
Article
3102 Background: Recent work from our laboratory demonstrated that T cell-derived acetylcholine induces vasodilation and increases T cell migration to infected tissues in response to viral infection (Cox et al. Science 2019). Choline acetyltransferase catalyzes the production of acetylcholine from choline and acetyl-CoA, however acetylcholine is ch...
Article
Full-text available
Cell division and organismal development are exquisitely orchestrated and regulated processes. The dysregulation of the molecular mechanisms underlying these processes may cause cancer, a consequence of cell-intrinsic and/or cell-extrinsic events. Cellular DNA can be damaged by spontaneous hydrolysis, reactive oxygen species, aberrant cellular meta...
Article
Full-text available
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Article
Regulatory T cells (Tregs) maintain immune homeostasis and prevent autoimmunity. Serine stimulates glutathione (GSH) synthesis and feeds into the one-carbon metabolic network (1CMet) essential for effector T cell (Teff) responses. However, serine’s functions, linkage to GSH, and role in stress responses in Tregs are unknown. Here, we show, using mi...
Article
The metalloprotease ADAM17 (a disintegrin and metalloprotease 17) regulates EGF-receptor and TNFα signaling, thereby not only protecting the skin and intestinal barrier, but also contributing to autoimmunity. ADAM17 can be rapidly activated by many stimuli through its transmembrane domain (TMD), with the seven membrane-spanning inactive Rhomboids (...
Article
Full-text available
Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors for which there is currently no effective treatment. Some of these tumors combine gain-of-function mutations in ACVR1, PIK3CA, and histone H3-encoding genes. The oncogenic mechanisms of action of ACVR1 mutations are currently unknown. Using mouse models, we demonstrate...
Conference Paper
Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i), in combination with hormonal therapies, have become standard of care for the treatment of estrogen receptor-positive (ER+)/HER2-negative metastatic breast cancer. Despite demonstrating significant improvements in progression-free survival, acquired resistance to these inhibitors invariably d...
Article
Full-text available
The metalloprotease ADAM17 (a disintegrin and metalloprotease 17) is a key regulator of tumor necrosis factor α (TNFα), interleukin 6 receptor (IL-6R), and epidermal growth factor receptor (EGFR) signaling. ADAM17 maturation and function depend on the seven membrane-spanning inactive rhomboid-like proteins 1 and 2 (iRhom1/2 or Rhbdf1/2). Most studi...
Article
Full-text available
Elucidating key factors that regulate immune-mediated pathology in vivo is critical for developing improved strategies to treat autoimmune disease and cancer. NK cells can exhibit regulatory functions against CD8+ T cells following viral infection. Here we show that while low doses of lymphocytic choriomeningitis virus (LCMV-WE) can readily induce...
Preprint
Full-text available
Mammals store memories in the nervous and immune systems. Sensory neurons have been implicated in enhancing neurological memory, but whether neurons participate during immunity to novel antigens is unknown. Here, mice rendered deficient in transient receptor potential vanilloid 1 (TRPV1)-expressing sensory neurons, termed nociceptors, fail to devel...
Article
Background: Toso, the FcR receptor (FcmR) for IgM, is a type I transmembrane protein belonging to the immunoglobulin gene superfamily. Toso is expressed in lymphocytes, and plays an important role in B cell development and survival. In normal B cells, Toso expression increases after B cell receptor (BCR) stimulation, and Toso enhances BCR signaling...
Article
Acetylcholine (ACh) is best known as a neurotransmitter and was the first such molecule identified. ACh signalling in the neuronal cholinergic system has long been known to regulate numerous biological processes (reviewed by Beckmann and Lips). In actuality, ACh is a ubiquitous signalling molecule that is produced by numerous non‐neuronal cell type...
Article
Chronic liver disease can induce prolonged activation of hepatic stellate cells, which may result in liver fibrosis. Inactive rhomboid protein 2 (iRhom2) is required for the maturation of A disintegrin and metalloprotease 17 (ADAM17, also called TACE), which is responsible for the cleavage of membrane-bound tumor necrosis factor–α (TNF-α) and its r...
Article
Lysophosphatidic acid (LPA) is a potent bioactive phospholipid that stimulates a variety of cellular responses by acting on cognate G protein-coupled receptors (GPCRs). There is increasing evidence that LPA signaling reprograms gene expression, but the GPCR-induced pathways connecting LPA receptor stimulation to downstream transcription factors are...
Article
Full-text available
Age-related macular degeneration (AMD) is an expanding problem as longevity increases worldwide. While inflammation clearly contributes to vision loss in AMD, the mechanism remains controversial. Here we show that neutrophils are important in this inflammatory process. In the retinas of both early AMD patients and in a mouse model with an early AMD...
Preprint
Full-text available
The proper communication between gut and brain is pivotal for the maintenance of health and dysregulation of the gut brain axis can lead to several clinical disorders. Also, in Parkinson's disease (PD) 85 percentage of all patients experienced constipation long before showing any signs of motor phenotypes. For differential diagnosis and when it com...
Article
Full-text available
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Article
The spindle assembly checkpoint (SAC) maintains genomic integrity. A key component is threonine tyrosine kinase (TTK, also known as Mps1). TTK antagonism is hypothesized to cause genomic instability and cell death. Interrogating The Cancer Genome Atlas (TCGA) revealed high TTK expression in lung adenocarcinomas and squamous cell cancers versus the...
Article
Full-text available
CFI-400945 is a first-in-class oral inhibitor of polo-like kinase 4 (PLK4) that regulates centriole duplication. Primary objectives of this first-in-human phase 1 trial were to establish the safety and tolerability of CFI-400945 in patients with advanced solid tumours. Secondary objectives included pharmacokinetics, pharmacodynamics, efficacy, and...
Conference Paper
Background/Purpose: Lung cancer remains the leading cause of cancer-related death. Concurrent chemoradiation is the standard of care for locally advanced non-small cell lung cancer (NSCLC). Despite advancements in treatment, local control remains an issue and survival is suboptimal, highlighting the need for novel therapeutic approaches. Polo-like...
Article
Full-text available
Myeloid cells contribute to tumor progression, but how the constellation of receptors they express regulates their functions within the tumor microenvironment (TME) is unclear. We demonstrate that Fcmr (Toso), the putative receptor for soluble IgM, modulates myeloid cell responses to cancer. In a syngeneic melanoma model, Fcmr ablation in myeloid c...
Article
Full-text available
Significance Polo-like kinase 4 (PLK4), a known cell cycle regulatory protein, localizes to the centrosome during S-phase and facilitates centrosome duplication. We show that phospho-serine305-PLK4 is subsequently redistributed to kinetochores (metaphase and anaphase), midzone during cleavage furrow formation (anaphase and telophase), and midbody (...
Article
Significance Immunotherapies targeting the programmed death-1 (PD-1) and its ligand PD-L1 have recently been combined with standard chemotherapy to potentiate the treatment of solid tumors, including triple negative breast cancer (TNBC). Reactive oxygen species (ROS) have been directly linked to the cytotoxic effects of chemotherapy. Here we report...
Article
ChAT-ty T cells fight viral infection The neurotransmitter acetylcholine (ACh) is involved in processes such as muscle contraction, neuron communication, and vasodilation. Along with neurons, a population of immunological T cells and B cells express the enzyme choline acetyltransferase (ChAT), which catalyzes the rate-limiting step of ACh productio...
Article
Full-text available
Significance Basal-like/BRCA1-associated breast cancer (BC) is a very aggressive form of BC that frequently occurs in young women, with devastating effects. Since tailored therapies are lacking for this type of tumor, scientists and clinicians are searching for weaknesses that can be therapeutically exploited. Here we describe the role of the trans...
Article
Full-text available
Background: Adaptive immunity is crucial in cardiovascular and renal inflammation/fibrosis upon hyperactivation of mineralocorticoid receptor. We have previously demonstrated that dendritic cells can respond to mineralocorticoid receptor activation, and the neutrophil gelatinase-associated lipocalin (NGAL) in dendritic cells is highly increased dur...
Article
In this issue of Cancer Cell, Ogiwara et al. describe a novel link between the epigenetic regulator ARID1A and glutathione metabolism in cancer that is mediated by regulation of the cystine/glutamate transporter XCT. This work reveals that synthesis of reduced glutathione is a metabolic dependency of cancers with ARID1A-inactivating mutations.
Article
Full-text available
Abstract Previous research has suggested that thyroid hormone receptor alpha 1 (THRα1), a hormone responsive splice variant, may play a role in breast cancer progression. Whether THRα1 can be exploited for anti-cancer therapy is unknown. The antiproliferative and antitumor effects of dronedarone, an FDA-approved anti-arrhythmic drug which has been...
Article
Full-text available
Macrophage cytokine production is regulated by neural signals, for example in the inflammatory reflex. Signals in the vagus and splenic nerves are relayed by choline acetyltransferase+ T cells that release acetylcholine, the cognate ligand for alpha7 nicotinic acetylcholine subunit-containing receptors (α7nAChR), and suppress TNF release in macroph...
Article
Full-text available
Significance Expression in cancer cells of novel proteins generated by mutations in the TP53 gene is an important prognostic factor; however, how p53 mutants promote cancer progression is largely unknown. Here, we describe a molecular mechanism of gain-of-function by mutant p53 in hypoxic non-small cell lung cancer (NSCLC) cells. We identified the...
Article
Lipocalin-2 (LCN2) is an adipokine previously described for its contribution to numerous processes including innate immunity and energy metabolism. LCN2 has also been demonstrated to be an extracellular matrix (ECM) regulator through its association with the ECM protease matrix metalloproteinase-9 (MMP-9). With the global rise in obesity and the as...
Article
Deregulation of the cell cycle is a hallmark of cancer that enables limitless cell division. To support this malignant phenotype, cells acquire molecular alterations that abrogate or bypass control mechanisms in signaling pathways and cellular checkpoints that normally function to prevent genomic instability and uncontrolled cell proliferation. Con...
Article
Despite current treatments, lung cancers remain a major public health problem. Innovative ways are needed to treat or prevent these cancers. Centrosomes are critical for fidelity of mitosis. Abnormal centrosome numbers can cause aberrant mitosis and cell death. Polo-like kinase 4 (PLK4) is a serine/threonine kinase regulating centriole duplication...
Article
Full-text available
Hemophilic arthropathy (HA) is a debilitating degenerative joint disease that is a major manifestation of the bleeding disorder hemophilia A. HA typically begins with hemophilic synovitis that resembles inflammatory arthritides, such as rheumatoid arthritis, and frequently results in bone loss in patients. A major cause of rheumatoid arthritis is i...
Data
Cellular composition of DRG neuron preparations. The principal DRG cell types in the sensory neuron preparations isolated from DRGs collected from alum-injected and alum + KLH-immunized mice include neuronal cells: peptidergic nociceptor (PEP) cells, non-peptidergic nociceptor (NP) cells, and neurofilament containing (NF) cells, and non-neuronal (N...
Article
The molecular mechanisms whereby CD8+T cells become "exhausted" in the tumor microenvironment remain unclear. Programmed death ligand-1 (PD-L1) is upregulated on tumor cells and PD-1-PD-L1 blockade has significant efficacy in human tumors; however, most patients do not respond, suggesting additional mechanisms underlying T cell exhaustion. B7 super...