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Yehuda G. Assaraf

Yehuda G. Assaraf

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Education/ Resume:

Postdoctoral Research, 1986-1990, Department of Biological Sciences, Stanford University, Stanford, California.

Mentor: Prof. Robert T. Schimke.

Ph.D., 1987, Departments of Molecular Biology and Parasitology, Hebrew University, Hadassah Medical School, Jerusalem, Israel. Mentors: Prof. Uriel Bachrach and Prof. Dan T. Spira.

B.Sc. in Biology (Summa Cum Laude), 1982, Hebrew University, Jerusalem, Israel.

Research Summary:

Intrinsic and acquired resistance to chemotherapeutic agents remains a major impediment towards curative cancer therapyofvarious human malignancies. Hence, research in our lab focuses on deciphering the molecular mechanisms underlying anticancer drug resistance in culturedtumor cells as well as unravelling the molecular basis of chemoresistance in individual cancer patients. Based on the discovery of such mechanisms, we are developing novel strategies to overcome well-defined modalities of anticancer drug resistance thatwill pave the way towards efficacious personalized medicine.

Awards:

The Hershel and Hilda Rich Innovation Award, Technion-Israel Institute of Technology, 2010, 2014.

Incumbent of the Sylvia and Alexander Hassan Academic Chair, Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel, since 2011.

The KNAW Award of the Royal Netherlands Academy of Arts and Sciences for Visiting Professors, Cancer Center of Amsterdam, The Netherlands, 2010.

Congress Award of the 11th World Congress on Advances in Oncology and 9th International Symposium on Molecular Medicine, Hersonissos, Crete, Greece, October 14th, 2006.

Head, The Fred Wyszkowski Cancer Research Lab, Faculty of Biology, Technion, since 2006.

The First V-ICI Keynote Award Lecture, Amsterdam, The Netherlands, 2006.

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Key Publications:
  • Assaraf, Y.G.,Brozovic, A., Gonçalves, A.C., Jurkovicova, D., Linē, A., Machuqueiro, M., Saponara, S., Sarmento-Ribeiro, A.B., Xavier, C.P.R., Vasconcelos, M.H. (2019) The multi-factorial nature of clinical multidrug resistance in cancer.Drug Resist. Updat., 2019 Sep 17;46:100645. doi: 10.1016/j.drup.2019.100645.
  • Zhitomirsky, B., and Assaraf, Y.G. (2016) Lysosomes as mediators of drug resistance in cancer. Drug Resist. Updat.24: 23-33.
  • Golan, Y.,Itsumura, N., Glaser, F., Berman, F., Kambe, T., and Assaraf, Y.G. (2016) Molecular basis of transient neonatal zinc deficiency: novel ZnT2 mutations disrupting zinc binding and permeation. Biol. Chem. 24: 13549-13559.
  • Golan, Y., Berman, B., and Assaraf, Y.G. (2015)Heterodimerization, altered subcellular localization and function of multiple zinc transporters in viable cells using bimolecular fluorescence complementation. Biol. Chem., 290:9050-9063.
  • Zhitomirsky, B., and Assaraf, Y.G. (2015) Lysosomal sequestration of hydrophobic weak base chemotherapeutics triggers lysosomal biogenesis and lysosome-dependent cancer multidrug resistance. Oncotarget 6:1143-1156.
  • Lasry, I., Golan, Y., Berman, B., Amram, N., Glazer, F., and Assaraf, Y.G. (2014) In situ dimerization of multiple wild type and mutant zinc transporters in live cells using bimolecular fluorescence complementation. Biol. Chem.,289:7275-7292.
  • Raz, S., Sheban, D., Gonen, N., Stark, M., Berman, B., and Assaraf, Y.G. (2014) Severe hypoxia induces complete antifolate resistance in carcinoma cells due to cell cycle arrest. Cell Death &, 20;5: e1067.
  • Lasry, I.,Seo, Y.A., Ityel, H., Shalva, , Pode-Shakked, B. Glaser, F., Berman, B.,Berezovsky, I., Goncearenco, A., Klar, A., Levy, J., Anikster, Y., Kelleher, S.L., and Assaraf, Y.G.(2012) A dominant negative heterozygous G87R mutation in ZnT-2 (SLC30A2) results in transient neonatal zinc deficiency. J. Biol. Chem.287: 29348-29361.
  • Adar, Y., Stark, M., Bram, E.E.,Nowak-Sliwinska,, van den Bergh, H., Skladanowski, A., Griffioen, A.W., and Assaraf, Y.G. (2012) Imidazoacridinone-dependent lysosomal photodestruction: a pharmacologicalTrojan horse approach to eradicate multidrug resistant cancers. Cell Death & Dis.3: e293.
  • Stark, M., Bram, E.E., Akerman, M., Mandel-Gutfreund, Y., and Assaraf, Y.G. (2011) hnRNP H1/H2-dependent unsplicing of thymidine phosphorylase results in anticancer drug resistance. Biol. Chem. 286:3741-3754.
  • Gonen, N., and Assaraf, Y.G. (2010) The obligatory intestinal folate transporter PCFT (SLC46A1) is regulated by nuclear respiratory factor 1 (NRF-1). Biol. Chem.285: 33602-33613.
  • Bram, E.E., Stark, M., Raz, S., and Assaraf, Y.G. (2009) Chemotherapeutic drug-induced ABCG2 promoter demethylation as a novel mechanism of acquired multidrug resistance. Neoplasia11: 1359-1370.
  • Bram, E.E., Adar, Y., Mesika, N.,Sabisz, M., Skladanowski, A., and Assaraf, Y.G. (2009) Structural determinants of imidazoacridinones facilitating antitumor cytotoxicity are crucial for substrate recognition by ABCG2. Pharmacol. 75:1149-1159.
  • Stark, M., Wichman, C., Avivi, I., and Assaraf, Y.G. (2009) Aberrant splicing of folylpolyglutamate synthetase as a novel mechanism of antifolate resistance in leukemia. Blood113:4362-4369.
  • Lasry, I., Berman, B.,Straussberg, R., Sofer, Y., Bessler, H., Sharkia, M., Glaser, F., Jansen, G., Drori, S., and Assaraf, Y.G. (2008) A novel loss of function mutation in the proton-coupled folate transporter from a patient with hereditary folate malabsorption reveals that Arg 113 is crucial for function. Blood112: 2055-2061.
  • Bram, E., Ifergan, I., Grimberg, M., Lemke, K., Skladanowski, A., and Assaraf, Y.G. (2007) C421 allele-specific ABCG2 gene amplification in human lung cancer cells with resistance to the novel triazoloacridone antitumor agent C-1305. Pharmacol.74: 41-53.
  • Kaufman, Y., Ifergan, I., Rothem, L., Jansen, G., and Assaraf, Y.G. (2006) Coexistence of multiple mechanisms of PT523-resistance in human leukemia cells harboring three reduced folate carrier alleles: transcriptional silencing, inactivating mutations and allele loss. Blood 107: 3288-3294.
  • Stark, M., and Assaraf, Y.G. (2006) Loss of Sp1 function via inhibitory phosphorylation in antifolate-resistant human leukemia cells with down-regulation of the reduced folate carrier. Blood107: 708-715.
  • Ifergan, I., Scheffer, G.L., and Assaraf, Y.G. (2005) Novel extracellular vesicles mediate an ABCG2-dependent anticancer drug sequestration and resistance. Cancer Res.65:10952-10958.
  • Shafran, A., Ifergan, I., Bram, E., Jansen, G., Kathmann, I., Peters, G.J., Robey, R.W., Bates, S.E., and Assaraf, Y.G. (2005) ABCG2 harboring the Gly482 mutation confers high level resistance to hydrophilic antifolates. Cancer Res.65:8414-8422.
  • Ifergan, I., Jansen, G., and Assaraf, Y.G. (2005) Cytoplasmic confinement of breast cancer resistance protein (BCRP/ABCG2) as a novel mechanism of adaptation to short-term folate deprivation.

            Mol. Pharmacol.67: 1349-1359.

  • Rothem, L., Stark, M., and Assaraf, Y.G. (2004) Impaired CREB-1 phosphorylation in antifolate-resistant cell lines with down regulation of the reduced folate carrier gene. Pharmacol.66: 1536-1543.
  • Fotoohi, K., Jansen, G., Assaraf, Y.G., Rothem, L., Stark, M.,Kathmann, I., Gregorczyk, J., Peters, G.J., and Albertioni, F. (2004) Disparate mechanisms of antifolate resistance provoked by methotrexate and its metabolite 7-hydroxymethotrexate in leukemia cells: implications for efficacy of methotrexate therapy. Blood 104: 4194-4201.
  • Ifergan, I., Shafran, A., Jansen, G.,Hooijberg, J.H., Scheffer, G.L., and Assaraf, Y.G. (2004) Folate deprivation results in the loss of breast cancer resistance protein (ABCG2) expression: a role for BCRP in cellular folate homeostasis. Biol. Chem.279: 25527-25534.
  • Kaufman, Y., Drori, S., Cole, P.D., Kamen, B.A., Sirota, J., Ifergan, I., Rechavi, G., Toren, A., Weyl Ben-Arush, M., Elhasid, R., Sahar, D., Kaspers, G.J.L., Matherly, L.H., Jansen, G., and Assaraf, Y.G. (2004) Reduced folate carrier mutations are not the mechanism underlying methotrexate resistance in childhood acute lymphoblastic leukemia. Cancer100: 773-782.
  • Rothem, L., Stark, M., Kaufman, Y.,Mayo, L., and Assaraf, Y.G. (2004) Reduced folate carrier gene silencing in multiple antifolate-resistant tumor cell lines is due to a simultaneous loss of function of multiple transcription factors but not promoter methylation. Biol. Chem.279: 374-384.
  • Ifergan, I.,Meller, I., Issakov, J., and Assaraf, Y.G. (2003) Reduced folate carrier protein expression in osteosarcoma: implications for the prediction of tumor chemosensitivity. Cancer 98: 1958-1966.
  • Stark, M., Rothem, L., Scheffer, G.L., Jansen, G., Goldman, I.D., and Assaraf, Y.G. (2003) Antifolate resistance associated with loss of MRP1 expression and function in Chinese hamster ovary cells with markedly impaired export of folate and cholate. Pharmacol. 64: 220-227.
  • Rothem, L., Aronheim, A., and Assaraf, Y.G. (2003) Alterations in the expression of transcription factors and the reduced folate carrier as a novel mechanism of antifolate resistance in human leukemia cells.
  • Biol. Chem. 278: 8935-8941.
  • Liani, E., Rothem, L.,Bunni, M.A., Smith, C.A., Jansen, G., and Assaraf, Y.G. (2003) Loss of folylpoly-γ-glutamate synthetase activity is a dominant mechanism of resistance to polyglutamylation-dependent novel antifolates in multiple human leukemia sublines. J. Cancer103: 587-599.
  • Rothem, L., Ifergan, I., Kaufman, Y., Priest, D.G., Jansen, G., and Assaraf, Y.G. (2002) Resistance to multiple novel antifolates is mediated via defective drug transport resulting from clustered mutations in the reduced folate carrier gene in human leukemia cells. J. 367: 741-750.
  • Drori, S., Jansen, G., Mauritz, R., Peters, G.J. and Assaraf, Y.G. (2000) Clustering of mutations in the first transmembrane domain of the human reduced folate carrier in GW1843U89-resistant leukemia cells with impaired antifolate transport and augmented folate uptake. Biol. Chem. 275: 30855-30863.
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Recent Publications:
  • Stark, M., Raz, S. andAssaraf, Y.G. (2021) Folylpoly-ɣ-glutamate synthetase association to the cytoskeleton: Implications to folate metabolon compartmentalization. Journal of Proteomics. PubMed
  • Levin, M., Stark, M., Ofran, Y. and Assaraf, Y.G. (2021) Deciphering molecular mechanisms underlying chemoresistance in relapsed AML patients: towards precision medicine overcoming drug resistance. Cancer Cell Int. 21(1):53.  PubMed
  • Stark, M., Silva, T.F.D.,Levin, G., Machuqueiro, M. and Assaraf, Y.G. (2020) The lysosomotropic activity of hydrophobic weak base drugs is mediated via their intercalation into the lysosomal membrane. Cells. 9(5), 1082. PubMed
  • Lehvy, A.I., Horev, G., Golan, Y., Glaser, F., Shammai, Y. and Assaraf, Y.G. (2019) Alterations in ZnT1 expression and function lead to impaired intracellular zinc homeostasis in cancer.Cell Death Discov. 5:144. PubMed
  • Golan, Y., Alhadeff, R., Warshel, A. and Assaraf, Y.G. (2019) ZnT2 is an electroneutral proton-coupled vesicular antiporter displaying an apparent stoichiometry of two protons per zinc ion. PLoSComput Biol.   15(3):e1006882.  PubMed
  • Levin, M., Stark, M., Berman, B. andAssaraf, Y.G. (2019) Surmounting Cytarabine-resistance in acute myeloblastic leukemia cells and specimens with a synergistic combination of hydroxyurea and azidothymidine. Cell Death & Disease. 10(6):390.  PubMed
  • Zhitomirsky, B., Yunaev, A., Kreiserman, R., Kaplan, A., Stark, M., and Assaraf, Y.G. (2018) Lysosomotropic drugs activate TFEB via lysosomal membrane fluidization and consequent inhibition of mTORC1 activity. Cell Death and Disease, Dec 13;9(12):1191. doi: 10.1038/s41419-018-1227-0PubMed
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