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Research Overview

Learn more:The Kanarek Lab

通过r metabolism is a rapidly growing field within the cancer biology scientific community. Within this field, one-carbon metabolism is particularly interesting due to its central role in several vital metabolic pathways. One-carbon metabolism requires folate, an enzymatic cofactor that is known for its key role in RNA and DNA production. Folate is essential for proliferation and for RNA biosynthesis; therefore, it is vital in all cells and tissues, regardless of proliferation state. While folate is a key cofactor essential for all living cells and is a targetable vulnerability in cancer cells, our understanding of its homeostasis and usage control is rudimentary.

遗传perturba下来博士卡娜里克和她的团队将使用tions, biochemical assays, molecular biology and metabolite profiling for a comprehensive study of folate homeostasis at the cellular level and the whole-organism level. The Kanarek lab investigates folate utilization by various cell types and tissues and explores the cancer-specific survival mechanisms of folate-deprived cells in culture and in vivo. In addition, some of the work in the lab is dedicated to projects that involve clinical follow-up on findings regarding the role of the histidine degradation pathway in the response of cancer cells to the chemotherapy methotrexate. The long-term goals of Dr. Kanarek’s work are (i) to significantly improve anti-cancer chemotherapy through the development of our understanding of folate metabolism and the identification of targetable proteins in folate sensing, metabolism and whole-body homeostasis, and (ii) to characterize folate regulation pathways relevant for healthy individuals as well as patients that suffer from folate deficiency related disorders.

Methods used in theKanarek Labinclude: 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.

Selected Publications

  1. Kanarek N, Keys HR, Cantor JR, Lewis CA, Chan SH, Kunchok T, Abu-Remaileh M, Freinkman E, Schweitzer LD and Sabatini DM Histidine catabolism is a major determinant of methotrexate sensitivity. Nature 2018 Jul;559(7715):632-636. doi: 10.1038/s41586-018-0316-7. Epub 2018 Jul 11.
  2. Cantor JR, Abu-Remaileh M, Kanarek N, Freinkman E, Gao X, Louissaint Jr. A, Lewis CA, Sabatini DM, Physiologic Medium Rewires Cellular Metabolism and Reveals Uric Acid as an Endogenous Inhibitor of UMP Synthase. Cell 2017 169 (2): 258-272.e17
  3. Shaul YD, Freinkman E, Comb WC, Cantor JR, Tam WL, Thiru P, Kim D, Kanarek N, Pacold ME, Chen WW, Bierie B, Possemato R, Reinhardt F, Weinberg RA, Yaffe MB, Sabatini DM. Dihydropyrimidine accumulation is required for the epithelial-mesenchymal transition. Cell 2014 Aug 28;158(5):1094-109. doi: 10.1016/j.cell.2014.07.032.
  4. Horwitz E, Stein I, Andreozzi M, Nemeth J, Shoham A, Pappo O, Schweitzer N, Tornillo L, Kanarek N, Quagliata L, Zreik F, Porat RM, Finkelstein R, Reuter H, Koschny R, Ganten T, Mogler C, Shibolet O, Hess J, Breuhahn K, Grunewald M, Schirmacher P, Vogel A, Terracciano L, Angel P, Ben-Neriah Y, Pikarsky E. Human and mouse VEGFA-amplified hepatocellular carcinomas are highly sensitive to sorafenib treatment. Cancer Discov. 2014 Mar 31.
  5. Kanarek N, Grivennikov S, Leshets M, Horwitz E, Pagano M, Pikarsky E, Karin M, Ghosh S, and Ben-Neriah Y. A critical role for IL-1ß in DNA damage-induced colitis. Proc Natl Acad Sci U S A. 2014 Feb 11;111(6):E702-11. doi: 10.1073/pnas.1322691111. Epub 2014 Jan 27.
  6. Kanarek N and Ben-Neriah Y. Regulation of NF-?B by Ubiquitination and Degradation of the I?Bs. Immunol Rev. 2012 Mar;246(1):77-94.
  7. Duan S, Skaar JF, Toschi A, Kanarek N, Ben-Neriah Y, and Pagano M. 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.
  8. Kanarek N, Horwitz E, Mayan I, Leshets M, Cojocaru G, Davis M, Tsuberi BZ, Pikarsky E, Pagano M, and Ben-Neriah Y. Spermatogenesis rescue in a mouse deficient for the ubiquitin ligase SCF?-TrCP by single substrate depletion. Genes and Dev. Mar 1, 2010; 24 (5)
  9. Kanarek N, London N, Schueler-Furman O, and Ben-Neriah Y. Ubiquitination and Degradation of the Inhibitors of NF-kB. Cold Spring Harb Perspect Biol. February 2010;2:a000166
  10. Zach N, Kanarek N, Inbar D, Grinvald Y, Milestein T, Vaadia E. Segregation between acquisition and long-term memory in sensorimotor learning. Eur J Neurosci. 2005

Publications
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