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.
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.
Acetate reprograms gut microbiota during alcohol consumption
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
Metabolic 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
Spontaneous hydrolysis and spurious metabolic properties of a-ketoglutarate esters.
Proteomic screens for suppressors of anoikis identify IL1RAP as a promising surface target in Ewing sarcoma.
Autophagy is required for proper cysteine homeostasis in pancreatic cancer through regulation of SLC7A11.
Proceedings of the National Academy of Sciences of the United States of America
Transporters at the Interface between Cytosolic and Mitochondrial Amino Acid Metabolism.
Respiratory Supercomplexes Promote Mitochondrial Efficiency and Growth in Severely Hypoxic Pancreatic Cancer.
Disruption of redox homeostasis for combinatorial drug efficacy in K-Ras tumors as revealed by metabolic connectivity profiling.
Cancer & metabolism
Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I.
Selective Alanine Transporter Utilization Creates a Targetable Metabolic Niche in Pancreatic Cancer.
Deuterium Tracing to Interrogate Compartment-Specific NAD(P)H Metabolism in Cultured Mammalian Cells.
Methods in molecular biology (Clifton, N.J.)
KRAS4A directly regulates hexokinase 1.
Glutamine 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
Posttranscriptional Upregulation of IDH1 by HuR Establishes a Powerful Survival Phenotype in Pancreatic Cancer Cells.
LKB1 promotes metabolic flexibility in response to energy stress.
Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models.
Distinct Metabolic States Can Support Self-Renewal and Lipogenesis in Human Pluripotent Stem Cells under Different Culture Conditions.
Reductive carboxylation supports redox homeostasis during anchorage-independent growth.
Chasing One-Carbon Units to Understand the Role of Serine in Epigenetics.
Loss of succinate dehydrogenase activity results in dependency on pyruvate carboxylation for cellular anabolism.
Metabolic consequences of oncogenic IDH mutations.
Pharmacology & therapeutics
Regulation of substrate utilization by the mitochondrial pyruvate carrier.
Tracing compartmentalized NADPH metabolism in the cytosol and mitochondria of mammalian cells.
IDH1 mutations alter citric acid cycle metabolism and increase dependence on oxidative mitochondrial metabolism.
Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells.
Identification and mechanistic studies of a novel ubiquitin E1 inhibitor.
Journal of biomolecular screening
Largazole and its derivatives selectively inhibit ubiquitin activating enzyme (e1).
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 & Awards
American Cancer Society Postdoctoral Fellowship (2019-2020)
Siebel Scholar (2016)
Achievement Reward for College Scientists (2016)Research Group Members
Sadie Gale, Undergraduate research assistant
Amrit Johal, Masters Student
Nisha Johal, MSc Student
Abisola Kehinde, PhD Student
Jessica Koe, Masters Student
Kabelo Ntsala, WorkLearn Student
Cindy Ong, Research Assistant
Kiana Pashaoskooie, Undergraduate Researcher