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Pathology Research

Research Overview

The Kanarek Laboratory is interested in folate metabolism. It is surprising that this essential vitamin, so famous for its key role in development, hematopoiesis and cancer progression, is still a mystery when it comes to its cellular and whole-body sensing and homeostasis.

The Kanarek lab applies genetic perturbations, biochemical assays, molecular biology, functional genomic screens, and metabolite profiling by mass spectrometry in cell-culture systems and in vivo to study basic folate biology including folate metabolism, folate-related signal transduction, the oncogenic role of folate and folate homeostasis in normal physiology and pathological conditions.

Methods used in the Kanarek Lab include: metabolite profiling by mass spec, CRISPR/Cas9 functional genomic screens, CRISPR-based individual gene knockouts, in vivo tumor models, molecular biology tools and biochemistry.

Research Background

A native of Jerusalem, Israel, Dr. Naama Kanarek trained at the Hebrew University, where she earned a BSc (2004) in medical science, an MSc in proteomics and microbiology (2008), and a PhD (2012) in immunology and cancer research with one year at Columbia University Medical Center in New York. Dr. Kanarek’s postdoctoral research (2012-2019) was performed under the supervision of Prof. David M. Sabatini at MIT’s Whitehead Institute.

In the laboratory of Prof. David M. Sabatini Naama became interested in the cancer metabolism field, and specifically, in folate metabolism. She studied the response of hematopoietic cancer cells to the anti-folate chemotherapeutic agent methotrexate using a genome-wide, loss-of-function CRISPR/Cas9-based screen. Through the screen Dr. Kanarek found that the histidine degradation pathway significantly influences the sensitivity of cancer cells to methotrexate and can be exploited to improve methotrexate efficacy through simple dietary intervention. Additionally, her findings raised the possibility that the histidine degradation pathway plays an uncharacterized key role in folate homeostasis through directing folate towards a putative storage form of folate.

Dr. Kanarek is the recipient of a number of awards and honors, including the Margaret and Herman Sokol Postdoctoral Award (2018), the Leukemia and Lymphoma Society New Idea Award (2017), the Hebrew University Women in Science Postdoctoral Award (2014), the Weizmann Institute Postdoctoral Award for Advancing Women in Science and a Revson Fellow of that program (2012), and the James Sivarsten Prize in Pediatric Cancer Research (2010). Her postdoctoral work was supported by fellowships from the American Association for Cancer Research (2016) and the European Molecular Biology Organization (2012).

As a postdoctoral fellow working mainly with pediatric cancer patients, Dr. Kanarek developed great care for these patients and deep understanding of their needs. She therefore established No Empty Bedsides (www.noemptybedsides.com), a charitable organization that helps find solutions for parents who, for personal or financial reasons, have difficulty remaining in hospital while their children undergo medical treatment.

Publications

  1. Retinoid X Receptor Signaling Mediates Cancer Cell Lipid Metabolism in the Leptomeninges. bioRxiv. 2024 Oct 15. View Abstract
  2. Technologies for Decoding Cancer Metabolism with Spatial Resolution. Cold Spring Harb Perspect Med. 2024 Sep 16. View Abstract
  3. Profiling metabolome of mouse embryonic cerebrospinal fluid following maternal immune activation. J Biol Chem. 2024 Oct; 300(10):107749. View Abstract
  4. A metabolic switch orchestrated by IL-18 and the cyclic dinucleotide cGAMP programs intestinal tolerance. Immunity. 2024 09 10; 57(9):2077-2094.e12. View Abstract
  5. Disrupting CD38-driven T cell dysfunction restores sensitivity to cancer immunotherapy. bioRxiv. 2024 Mar 26. View Abstract
  6. Folate depletion induces erythroid differentiation through perturbation of de novo purine synthesis. Sci Adv. 2024 Feb 02; 10(5):eadj9479. View Abstract
  7. Optimized Mass Spectrometry Detection of Thyroid Hormones and Polar Metabolites in Rodent Cerebrospinal Fluid. Metabolites. 2024 Jan 23; 14(2). View Abstract
  8. Metabolomics of Mouse Embryonic CSF Following Maternal Immune Activation. bioRxiv. 2023 Dec 24. View Abstract
  9. Optimized Mass Spectrometry Detection of Thyroid Hormones and Polar Metabolites in Rodent Cerebrospinal Fluid. bioRxiv. 2023 Dec 08. View Abstract
  10. Regulatory mechanisms of one-carbon metabolism enzymes. J Biol Chem. 2023 12; 299(12):105457. View Abstract
  11. Regulators of mitonuclear balance link mitochondrial metabolism to mtDNA expression. Nat Cell Biol. 2023 Nov; 25(11):1575-1589. View Abstract
  12. FDX1 regulates cellular protein lipoylation through direct binding to LIAS. J Biol Chem. 2023 09; 299(9):105046. View Abstract
  13. Simultaneous isolation of hormone receptor-positive breast cancer organoids and fibroblasts reveals stroma-mediated resistance mechanisms. J Biol Chem. 2023 08; 299(8):105021. View Abstract
  14. Defining diurnal fluctuations in mouse choroid plexus and CSF at high molecular, spatial, and temporal resolution. Nat Commun. 2023 06 22; 14(1):3720. View Abstract
  15. Correction: Maynard et al. Notes from the 2022 Folate, Vitamin B12, and One-Carbon Metabolism Conference. Metabolites 2023, 13, 486. Metabolites. 2023 Jun 14; 13(6). View Abstract
  16. Notes from the 2022 Folate, Vitamin B12, and One-Carbon Metabolism Conference. Metabolites. 2023 Mar 28; 13(4). View Abstract
  17. Genome-wide screens for mitonuclear co-regulators uncover links between compartmentalized metabolism and mitochondrial gene expression. bioRxiv. 2023 Feb 11. View Abstract
  18. FDX1 regulates cellular protein lipoylation through direct binding to LIAS. bioRxiv. 2023 Feb 04. View Abstract
  19. Cycloguanil and Analogues Potently Target DHFR in Cancer Cells to Elicit Anti-Cancer Activity. Metabolites. 2023 Jan 19; 13(2). View Abstract
  20. Choroid plexus-CSF-targeted antioxidant therapy protects the brain from toxicity of cancer chemotherapy. Neuron. 2022 10 19; 110(20):3288-3301.e8. View Abstract
  21. Copper induces cell death by targeting lipoylated TCA cycle proteins. Science. 2022 03 18; 375(6586):1254-1261. View Abstract
  22. Author Correction: Histidine catabolism is a major determinant of methotrexate sensitivity. Nature. 2022 Feb; 602(7895):E17-E18. View Abstract
  23. The antimicrobial drug pyrimethamine inhibits STAT3 transcriptional activity by targeting the enzyme dihydrofolate reductase. J Biol Chem. 2022 02; 298(2):101531. View Abstract
  24. Redox Metabolism Measurement in Mammalian Cells and Tissues by LC-MS. Metabolites. 2021 May 13; 11(5). View Abstract
  25. Integrative Metabolomics to Identify Molecular Signatures of Responses to Vaccines and Infections. Metabolites. 2020 Nov 30; 10(12). View Abstract
  26. Potential Benefits and Pitfalls of Histidine Supplementation for Cancer Therapy Enhancement. J Nutr. 2020 10 01; 150(Suppl 1):2580S-2587S. View Abstract
  27. NADH Ties One-Carbon Metabolism to Cellular Respiration. Cell Metab. 2020 04 07; 31(4):660-662. View Abstract
  28. Dietary modifications for enhanced cancer therapy. Nature. 2020 03; 579(7800):507-517. View Abstract
  29. Histidine catabolism is a major determinant of methotrexate sensitivity. Nature. 2018 07; 559(7715):632-636. View Abstract
  30. Physiologic Medium Rewires Cellular Metabolism and Reveals Uric Acid as an Endogenous Inhibitor of UMP Synthase. Cell. 2017 Apr 06; 169(2):258-272.e17. View Abstract
  31. Dihydropyrimidine accumulation is required for the epithelial-mesenchymal transition. Cell. 2014 Aug 28; 158(5):1094-1109. View Abstract
  32. Human and mouse VEGFA-amplified hepatocellular carcinomas are highly sensitive to sorafenib treatment. Cancer Discov. 2014 Jun; 4(6):730-43. View Abstract
  33. Critical role for IL-1ß in DNA damage-induced mucositis. Proc Natl Acad Sci U S A. 2014 Feb 11; 111(6):E702-11. View Abstract
  34. Regulation of NF-?B by ubiquitination and degradation of the I?Bs. Immunol Rev. 2012 Mar; 246(1):77-94. View Abstract
  35. mTOR generates an auto-amplification loop by triggering the ßTrCP- and CK1a-dependent degradation of DEPTOR. Mol Cell. 2011 Oct 21; 44(2):317-24. View Abstract
  36. Spermatogenesis rescue in a mouse deficient for the ubiquitin ligase SCF{beta}-TrCP by single substrate depletion. Genes Dev. 2010 Mar 01; 24(5):470-7. View Abstract
  37. Ubiquitination and degradation of the inhibitors of NF-kappaB. Cold Spring Harb Perspect Biol. 2010 Feb; 2(2):a000166. View Abstract
  38. Segregation between acquisition and long-term memory in sensorimotor learning. Eur J Neurosci. 2005 Nov; 22(9):2357-62. View Abstract

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