Prof. Uri Ben-David

Senior Lecturer (Assistant Professor), Department of Human Molecular Genetics & Biochemistry, Faculty of Medicine, Tel-Aviv University

Cancer Aneuploidy

Aneuploidy – the presence of an abnormal number of chromosomes in cancer cells — is characteristic of most tumors, and is rarely observed in normal tissues. It is not fully understood how aneuploidy contributes to tumor formation and progression. Moreover, there are currently no therapeutics that target this hallmark of cancer to  eliminate tumors. We apply a variety of genomic and functional approaches to studying this phenomenon.

Genomic evolution of cancer models

The study of the complex genetics of human cancer depends on reliable cancer model systems. However, these models reflect the biology of actual human tumors only to a certain extent, and they evolve in ways that pose both risks and opportunities for cancer research. We study the genomic stability and evolution of cancer model systems, in order to improve their use in basic research, with an emphasis on aneuploidy research.

Stem cells and cancer

Human stem cells share fundamental characteristics with human cancer cells, and thus make for a unique model system for the study of cancer genetics. We use human stem cells as a tool for aneuploidy research, taking advantage of their inherent chromosomal instability and of their amenability to genome editing.  We also use human stem cells as a tool for the identification of cancer vulnerabilities.

PUBLICATIONS

^# Corresponding author; * Equally-contributing first-author

 

ORIGINAL RESEARCH PAPERS

2020

Winkler T. and Ben-David U. Elevated ACE2 expression levels in tumor-adjacent tissues of cancer patients. International Journal of Cancer, 2020. doi: doi.org/10.1002/ijc.33145.

Enache O.M.*, Rendo V.*, Abdusamad M., Lam D., Davison D., Pal S., Currimjee N., Hess J., Sanson K., Pantel S., Nag A., Thorner A., Root D., Doench J.G., Vazquez F., Beroukhim R., Golub T.R., and Ben-David U.^# Cas9 activates the p53 pathway and selects for p53-inactivating mutations. Nature Genetics, 2020. doi: 10.1038/s41588-020-0623-4.

Corsello S.M., Nagari R.T., Spangler R.D., Rossen J., Kocak M., Bryan J.G., Humeidi R., Peck D., Wu X., Tang A.A., Wang V.M., Bender S.A., Lemire E., Narayan R., Montgomery P., Ben-David U., Chen Y., Rees M.G., Lyons N.J., McFarland J.M., Wong B.T., Wang L., Dumont N., O'Hearn P.J., Stefan E., Doench J.G., Greulich H., Meyerson M., Vazquez F., Subramanian A., Roth J.A., Bittker J.A., Boehm J.S., Mader C.C., Tsherniak A., and Golub T.R. Discovering the anticancer potential of non-oncology drugs by systematic viability profiling. Nature Cancer, 2020. doi: 10.1038/s43018-019-0018-6.

2018

Ben-David U., Siranosian B., Ha G., Tang H., Oren Y., Hinohara K., Strathdee c.A., Dempster J., Lyons N.J., Burns R., Nag A., Kugener G., Cimini B., Tsvetkov P., Maruvka Y.E., O’Rourke R., Garrity A., Tubelli A.A., Bandopadhayay P., Tsherniak A., Vazquez F., Wong B., Birger C., Ghandi M, Thorner A.R., Bittker J.A., Meyerson M., Getz G., Beroukhim R. and Golub T.R. Genetic and transcriptional evolution alters cancer cell line drug response. Nature, 2018, 560(7718):325-330. doi: 10.1038/s41586-018-0409-3.

Abdeen S.A., Ben-David U., Maly B. and Aqueilan R. Somatic loss of WWOX drives triple-negative breast cancer through perturbation of TP53. Cell Death & Disease, 2018, 9(8):832. doi: 10.1038/s41419-018-0896-z.

2017

Ben-David U., Ha G., Tseng Y.Y., Greenwald N.F., Oh C., Shih J., McFarland J.M., Wong B., Boehm J.S., Beroukhim R. and Golub T.R. Patient-derived xenografts undergo mouse-specific tumor evolution. Nature Genetics ,2017, 49(11):1567-1575. doi:10.1038/ng.3967.

2016

Bi W.L., Horowtiz P., Greenwald N., Abedalthagafi M., Agarwalla P.K., Gibson W.J., Mei Y, Schumacher S.E., Ben-David U., Chevalier A., Carter S.L., Tiao G., Brastianos P.K., Ligon A.H., Ducar M., MacConaill L.E., Laws E.R., Santagata S., Beroukhim R., Dunn IF. Landscape of genomic alterations in pituitary adenomas. Clinical Cancer Research, 2016, 23(7):1841-1851. doi: 10.1158/1078-0432.CCR-16-0790.

Aguirre A., Meyers R., Weir B., Vazquez F., Zhang C.Z., Ben-David U., Cook A., Ha G., Harrington W., Doshi M., Gill S., Xu H., Ali L., Jiang G., Pantel S., Lee Y., Goodale A., Cherniack A., Oh C., Kryukov G., Cowley G., Garraway L., Stegmaier K., Roberts C., Golub T.R., Meyerson M., Root D., Tsherniak A., and Hahn W. Genomic copy number dictates a gene-independent cell response to CRISPR-Cas9 targeting. Cancer Discovery, 2016, 6(8):914-29. doi: 10.1158/2159-8290.CD-16-0154.

Ben-David U., Ha G., Khadka P., Jin X., Wong B., Franke L. and Golub T.R. The landscape of chromosomal aberrations in breast cancer mouse models reveals driver-specific routes to tumorigenesis. Nature Communications, 2016, 7:12160. doi:10.1038/ncomms12160.

Lamm N., Ben-David U., Kerem B. and Benvenisty N. Genomic instability in human pluripotent stem cells arises from replicative stress and chromosome condensation defects. Cell Stem Cell, 2016, 18(2): 253-61.

2015

Ben-David U., Cowell Ian G., Austin Caroline C. and Benvenisty N. Controlling the survival of human pluripotent stem cells by small molecule-based targeting of topoisomerase II alpha. Stem Cells, 2015, 33(3): 1013-9. doi: 10.1002/stem.1888.

2014

Weissbein U., Ben-David U. and Benvenisty N. Virtual karyotyping reveals greater chromosomal stability in neural cells derived by transdifferentiation than those from stem cells. Cell Stem Cell, 2014, 15(6):687-91. doi: 10.1016/j.stem.2014.10.018.

Ben-David U., Arad G., Weissbein U., Mandefro B., Maimon A., Narwani K., Clark A.T., Andrews P.W., Benvenisty N., and Biancotti J.C. Aneuploidy induces profound changes in gene expression, proliferation and tumorigenicity of human pluripotent stem cells. Nature Communications, 2014, 5:4825, doi: 10.1038/ncomms5825.

Ben-David U.*, Biran A.*, Scaffidi P., Boehringer M., Meshorer E. and Benvenisty N. Elimination of undifferentiated cancer cells by pluripotent stem cell inhibitors. Journal of Molecular Cell Biology, 2014, 6(3):267-9. doi: 10.1093/jmcb/mju012.

Ben-David U. and Benvenisty N. Chemical ablation of tumor-initiating human pluripotent stem cells. Nature Protocols, 2014, 9(3):729-40. doi: 10.1038/nprot.2014.050.

2013

Ben-David U., Nudel N. and Benvenisty N. Immunologic and chemical targeting of the tight-junction protein Claudin-6 eliminates tumorigenic human pluripotent stem cells. Nature Communications, 2013, 4:1992. doi:10.1038/ncomms2992.

Ben-David U., Gan Q.F., Golan-Lev T., Arora P., Yanuka O., Oren Y.S., Leikin-Frenkel A., Graf M., Garippa R., Boehringer M., Gromo G. and Benvenisty N. Selective elimination of human pluripotent stem cells by an oleate synthesis inhibitor discovered in a high-throughput screen. Cell Stem Cell, 2013, 12(2):167-79. doi: 10.1016/j.stem.2012.11.015.

Lee P., Martin N.T., Nakamura K., Azghadi S., Amiri M., Ben-David U., Perlman S., Gatti R.A., Hu H. and Lowry W.E. SMRT compounds abrogate cellular phenotypes of Ataxia Telangiectasia in neural derivatives of patient specific hiPSCs. Nature Communications, 2013, 4:1824. doi:10.1038/ncomms2824.

Ben-David U., Mayshar Y. and Benvenisty N. Virtual karyotyping of pluripotent stem cells on the basis of their global gene expression profiles. Nature Protocols, 2013, 8(5): 989-97.  doi: 10.1038/nprot.2013.051.

2012

Ben-David U. and Benvenisty N. High prevalence of evolutionarily conserved and species-specific genomic aberrations in mouse pluripotent stem cells. Stem Cells, 2012, 30(4):612-22. doi: 10.1002/stem.1057.

2011

Ben-David U., Mayshar Y. and Benvenisty N. Large-scale analysis reveals acquisition of lineage-specific chromosomal aberrations in human adult stem cells. Cell Stem Cell, 2011, 9(2):97-102. doi: 10.1016/j.stem.2011.06.013.

2010

Mayshar Y.*, Ben-David U.*, Lavon N., Biancotti J.C., Yakir B., Clark A.T., Plath K., Lowry W.E. and Benvenisty N. Identification and classification of chromosomal aberrations in human induced pluripotent stem cells. Cell Stem Cell, 2010, 7(4):521-31. doi: 10.1016/j.stem.2010.07.017.

 

REVIEWS & PERSPECTIVES

 

2020

Rendo V., Enache O. and Ben-David U. ^# Adding to the CASeload: Unwarranted Cas9-induced activation of the p53 pathway. Mol Cell Oncol, 2020 (in press).

Ben-David U.^# and Amon A. Context is everything: aneuploidy in cancer. Nature Reviews Genetics, 2020, 21(1):44-62. doi: 10.1038/s441576-019-0171-x.

2019

Ben-David U. ^#, Beroukhim R. and Golub T.R. Genomic evolution of cancer models: perils and opportunities. Nature Reviews Cancer, 2019, 19(2):97-109. doi: 10.1038/s41568-018-0095-3.

2018

Odorico. J., Adams A., Melton D., Greenstein G., Hwa A., Nostro C., Rezania A., Oberholzer J., Pipeleers D., Yang L., Cowan C., Huangfu D., Egli D., Ben-David U., Vallier L., Grey S., Tang Q., Roep B., Ricordi C., Naji A., Orlando G., Anderson D., Poznansky M., Ludwig B., Tomei A., Greiner D., Graham M., Carpenter M., Migliaccio G., D’Amour K., Hering B., Piemonti L., Berney T., Rickels M., Kay T. and Markmann J. Report of the Key Opinion Leaders Meeting on Stem Cell-Derived Beta Cells. Transplantation, 2018, 102(8):1223-1229. doi: 10.1097/TP.0000000000002217.

2017

Andrews P.W., Ben-David U., Benvenisty N., Coffey P., Eggan K., Knowles B.B., Nagy A., Pera M., Reubinoff B., Rugg-Gunn P.J., Stacey G.N. Assessing the safety of human pluripotent stem cells (PSCs) and their derivatives for clinical applications. Stem Cell Reports, 2017, 9(1):1-4. doi: 10.1016/j.stemcr.2017.05.029.

2015

Heslop A.J., Hammond T.G., Santeramo I., Piella A.T., Hopp I., Zhou J., Baty R., Graziano, E.I., Bernabe P., Shaw D.A., Bunn I., Caron A., Skold P., Andrews P.W., Baxter M., Hay D., Hamdam J., Sethu S., Sharpe M.E., Patel S., Jones D.R., Reinhardt J., Danen E.H.J., Ben-David U., Stacey G., Bjorquist P., Rowe, C., Pellegrini G., Antoine D., Cross M.J., Murray P., Williams D., Kitteringham N.R., Park B.K. and Goldring C.E.P. Understanding the risks of stem cell-based therapeutics. Stem Cells Translational Medicine, 2015, 4(4):389-400. doi: 10.5966/sctm.2014-0110.

2014

Ben-David U.^# Genomic instability, driver genes and cell selection: Projections from cancer to stem cells. Biochim Biophys Acta, 2014, 1849(4):427-35. doi: 10.1016/j.bbagrm.2014.08.005.

Weissbein U., Benvenisty N. and Ben-David U.^# Genome maintenance in pluripotent stem cells. Journal of Cell Biology 2014, 204(2):153-63. doi: 10.1083/jcb.201310135.

2013

Ben-David U.^# Flowing through the CRISPR-CAScade: Will genome editing boost cell therapies? Molecular and Cellular Therapies, 2013, 1:3, doi:10.1186/2052-8426-1-3.

Ben-David U., Nissenbaum J. and Benvenisty N. New balance in pluripotency: reprogramming with lineage specifiers. Cell, 2013, 153(5): 939-40. doi: 10.1016/j.cell.2013.04.051.

2012

Ben-David U., Kopper O. and Benvenisty N. Expanding the boundaries of embryonic stem cells. Cell Stem Cell, 2012, 10(6):666-77. doi: 10.1016/j.stem.2012.05.003.

Ben-David U. and Benvenisty N. Analyzing the genomic integrity of stem cells. StemBook, 2012. doi: 10.3824/stembook.1.50.1, http://www.stembook.org.

Ben-David U., Mayshar Y. and Benvenisty N. Significant acquisition of chromosomal aberrations in human adult mesenchymal stem cells: Response to Sensenbé et al. Cell Stem Cell, 2012, 10(1):10-11. doi: 10.1016/j.stem.2011.12.007.

2011

Goldring C.E.P., Duffy P.A., Benvenisty N., Andrews P.W., Ben-David U., Eakins R., French N., Hanley N.A., Kelly L., Kitteringham N.R., Kurth J., Ladenheim D., Laverty H., McBlane J., Narayanan G., Patel S., Reinhardt J, Rossi A., Sharpe M. and Park K. Assessing the safety of stem cell therapeutics. Cell Stem Cell, 2011, 8(6):618-28. doi: 10.1016/j.stem.2011.05.012.

Ben-David U. and Benvenisty N. The tumorigenicity of human embryonic and induced pluripotent stem cells. Nature Reviews Cancer, 2011, 11(4): 268-77. doi: 10.1038/nrc3034.

2010

Ben-David U., Benvenisty N. and Mayshar Y. Genetic instability in human induced pluripotent stem cells: Classification of causes and possible safeguards. Cell Cycle, 2010, 9(23): 4603-4.

 

Grants

2020-2024             The United States – Israel Binational Science Foundation Resarch Grant (co-PI with Prof. Angelika Amon from MIT)

2020-2023             The Department of Defense (DoD) Peer Reviewed Cancer Research Program (PRCRP) Career Development Award

2020                       The Israel Cancer Association Research Grant

2020                       The Cancer Biology Research Center Research Grant

2019-2020             The Eimert Research Fund on Solid Tumors

2019-2022             The Azrieli Foundation Faculty Fellowship