Congratulations to the BC Children's Hospital Research Institute (BCCHR) and Women’s Health Research Institute (WHRI) investigators and their teams who were awarded funding through the Canadian Institutes of Health Research (CIHR) Fall 2021 Project Grant competition. Our research community received around $6 million in new research grants as principal investigators or co-investigators.
- Overview
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One of the main areas of research within my group involves identifying and characterizing specific transport proteins that are required by cells to fulfill their metabolic needs. Within this objective, we aim to understand what drives selective transporter expression in disease, how transporters function in specific physiological contexts, and how we can target the unique metabolic demands of cancer. We utilize biochemical and molecular biology techniques and develop quantitative mass spectrometry-based methods that include targeted and discovery metabolomics, stable-isotope tracing, and metabolic flux analysis to characterize the fate of key nutrients in diseased cells.
- Publications
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A Peptidisc-Based Survey of the Plasma Membrane Proteome of a Mammalian Cell
Molecular & Cellular Proteomics
Zhiyu Zhao and Arshdeep Khurana and Frank Antony and John W. Young and Keeley G. Hewton and Zora Brough and Tianshuang Zhong and Seth J. Parker and Franck Duong van Hoa
DOI: 10.1016/j.mcpro.2023.100588
08/2023Acetate reprograms gut microbiota during alcohol consumption
Nature Communications
Cameron Martino and Livia S. Zaramela and Bei Gao and Mallory Embree and Janna Tarasova and Seth J. Parker and Yanhan Wang and Huikuan Chu and Peng Chen and Kuei-Chuan Lee and Daniela Domingos Galzerani and Jivani M. Gengatharan and Asama Lekbua and Maxwell Neal and Rob Knight and Hidekazu Tsukamoto and Christian M. Metallo and Bernd Schnabl and Karsten Zengler
DOI: 10.1038/s41467-022-31973-2
08/2022Metabolic reprogramming of tumor-associated macrophages by collagen turnover promotes fibrosis in pancreatic cancer
Proceedings of the National Academy of Sciences
Madeleine M. LaRue and Seth Parker and Joseph Puccini and Michael Cammer and Alec C. Kimmelman and Dafna Bar-Sagi
DOI: 10.1073/pnas.2119168119
04/2022Spontaneous hydrolysis and spurious metabolic properties of a-ketoglutarate esters
Nature Communications
Seth J. Parker and Joel Encarnación-Rosado and Kate E. R. Hollinshead and David M. Hollinshead and Leonard J. Ash and Juan A. K. Rossi and Elaine Y. Lin and Albert S. W. Sohn and Mark R. Philips and Drew R. Jones and Alec C. Kimmelman
DOI: 10.1038/s41467-021-25228-9
08/2021Proteomic screens for suppressors of anoikis identify IL1RAP as a promising surface target in Ewing sarcoma.
Cancer discovery
DOI: 10.1158/2159-8290.cd-20-1690
PubMed: 34021002
05/2021Transporters at the Interface between Cytosolic and Mitochondrial Amino Acid Metabolism.
Metabolites
DOI: 10.3390/metabo11020112
PubMed: 33669382
02/2021Autophagy is required for proper cysteine homeostasis in pancreatic cancer through regulation of SLC7A11
Proceedings of the National Academy of Sciences
Subhadip Mukhopadhyay and Douglas E. Biancur and Seth J. Parker and Keisuke Yamamoto and Robert S. Banh and Joao A. Paulo and Joseph D. Mancias and Alec C. Kimmelman
DOI: 10.1073/pnas.2021475118
02/2021Respiratory Supercomplexes Promote Mitochondrial Efficiency and Growth in Severely Hypoxic Pancreatic Cancer.
Cell reports
DOI: 10.1016/j.celrep.2020.108231
PubMed: 33027658
10/2020Disruption of redox homeostasis for combinatorial drug efficacy in K-Ras tumors as revealed by metabolic connectivity profiling.
Cancer & metabolism
DOI: 10.1186/s40170-020-00227-4
PubMed: 33005401
09/2020Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I.
Nature
DOI: 10.1038/s41586-020-2229-5
PubMed: 32376951
04/2020Selective Alanine Transporter Utilization Creates a Targetable Metabolic Niche in Pancreatic Cancer.
Cancer discovery
DOI: 10.1158/2159-8290.cd-19-0959
PubMed: 32341021
04/2020Deuterium Tracing to Interrogate Compartment-Specific NAD(P)H Metabolism in Cultured Mammalian Cells.
Methods in molecular biology (Clifton, N.J.)
DOI: 10.1007/978-1-0716-0159-4_4
PubMed: 31893370
01/2020KRAS4A directly regulates hexokinase 1.
Nature
DOI: 10.1038/s41586-019-1832-9
PubMed: 31827279
12/2019Glutamine metabolism via glutaminase 1 in autosomal-dominant polycystic kidney disease.
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
DOI: 10.1093/ndt/gfx349
PubMed: 29420817
08/2018Posttranscriptional Upregulation of IDH1 by HuR Establishes a Powerful Survival Phenotype in Pancreatic Cancer Cells.
Cancer research
DOI: 10.1158/0008-5472.can-17-0015
PubMed: 28652247
06/2017LKB1 promotes metabolic flexibility in response to energy stress.
Metabolic engineering
DOI: 10.1016/j.ymben.2016.12.010
PubMed: 28034771
12/2016Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models.
Nature medicine
DOI: 10.1038/nm.4181
PubMed: 27643638
09/2016Distinct Metabolic States Can Support Self-Renewal and Lipogenesis in Human Pluripotent Stem Cells under Different Culture Conditions.
Cell reports
DOI: 10.1016/j.celrep.2016.06.102
PubMed: 27477285
07/2016Reductive carboxylation supports redox homeostasis during anchorage-independent growth.
Nature
DOI: 10.1038/nature17393
PubMed: 27049945
04/2016Chasing One-Carbon Units to Understand the Role of Serine in Epigenetics.
Molecular cell
DOI: 10.1016/j.molcel.2016.01.006
PubMed: 26799763
01/2016Loss of succinate dehydrogenase activity results in dependency on pyruvate carboxylation for cellular anabolism.
Nature communications
DOI: 10.1038/ncomms9784
PubMed: 26522426
11/2015Metabolic consequences of oncogenic IDH mutations.
Pharmacology & therapeutics
DOI: 10.1016/j.pharmthera.2015.05.003
PubMed: 25956465
05/2015Regulation of substrate utilization by the mitochondrial pyruvate carrier.
Molecular cell
DOI: 10.1016/j.molcel.2014.09.024
PubMed: 25458843
10/2014Tracing compartmentalized NADPH metabolism in the cytosol and mitochondria of mammalian cells.
Molecular cell
DOI: 10.1016/j.molcel.2014.05.008
PubMed: 24882210
05/2014IDH1 mutations alter citric acid cycle metabolism and increase dependence on oxidative mitochondrial metabolism.
Cancer research
DOI: 10.1158/0008-5472.can-14-0772-t
PubMed: 24755473
04/2014Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells.
Nature
DOI: 10.1038/nature12138
PubMed: 23665962
05/2013Largazole and its derivatives selectively inhibit ubiquitin activating enzyme (e1).
PloS one
DOI: 10.1371/journal.pone.0029208
PubMed: 22279528
01/2012Identification and mechanistic studies of a novel ubiquitin E1 inhibitor.
Journal of biomolecular screening
DOI: 10.1177/1087057111433843
PubMed: 22274912
01/2012 - Research
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Better tools to study amino acid metabolism and transport in intact cells
There are ~450 solute carrier (SLC) transporters that participate in the import and efflux of ions, amino acids, sugars, and cofactors required for metabolism. However, over 30% of
these SLCs are uncharacterized or poorly understood. Our research group is currently developing better molecular biology, imaging, and metabolomics tools that aim to advance our understanding of the function, localization, and cooperativity of amino acid transporters through uncoupling of transport from intracellular metabolism.Understand the metabolic advantage of selective, compartment-specific enzyme expression
The metabolic pathways that comprise eukaryotic metabolism are compartmentalized into distinct and specialized organelles (e.g. mitochondria, lysosomes, peroxisomes). Current metabolomics methods that extract bulk cellular metabolites fail to capture the compartmentalization of
intracellular metabolism. Our group aims to develop better methods to interrogate compartmentalized metabolic pathways. In this vein, we hope to understand how expression of specific enzyme isoforms may offer a selective advantage for cancer cells.Metabolic and transporter dependencies in childhood leukemia
Therapies that target the unique metabolism of leukemic blasts have demonstrated remarkable clinical success. However, toxicities can often limit the efficacy of anti-metabolic therapies
and relapse of therapeutic-resistant cancer can occur. My group aims to identify metabolic dependencies in childhood leukemia with a specific focus on relapsed cases. Furthermore, we are interested in targeting metabolite transport as a more direct approach over systemic metabolite depletion therapies that are currently employed.Honours & AwardsAmerican Cancer Society Postdoctoral Fellowship (2019-2020)
Siebel Scholar (2016)
Achievement Reward for College Scientists (2016)
Research Group MembersGeorgia Cheung, Research Assistant
Sadie Gale, Undergraduate research assistant
Keeley Hewton, Doctoral Candidate
Amrit Johal, Masters Student
Nisha Johal, Doctoral Student
Abisola Kehinde, PhD Student
Jessica Koe, Masters Student
Kiana Pashaoskooie, Undergraduate Researcher
Caiyun Wu, Directed Studies Student
Cassie Zhong, Graduate student
