Photo of David S. Pellman,  MD

David S. Pellman, MD

Dana-Farber Cancer Institute

Dana-Farber Cancer Institute
Phone: (617) 632-4918
Fax: (617) 632-6845


david_pellman@dfci.harvard.edu

David S. Pellman, MD

Dana-Farber Cancer Institute

EDUCATIONAL TITLES

  • Margaret M. Dyson Professor of Pediatric Oncology, Pediatrics, Harvard Medical School
  • Professor, Cell Biology, Harvard Medical School
  • Principal Investigator, Pediatric Oncology, Dana-Farber Cancer Institute

DF/HCC PROGRAM AFFILIATION

DF/HCC ASSOCIATIONS

  • Member, Center Scientific Council
  • Associate Director, Basic Science, Executive Committee

Research Abstract

Our laboratory aims to understand normal cell division mechanisms and to discover cell division defects that are unique to cancer cells. We take a range of approaches including genetics, functional genomics, biochemistry and live cell imaging. There are ongoing projects using yeast, tissue culture cells, and genetically engineered mice.

Our work on cytoskeletal dynamics is focused on the mechanism of chromosome segregation in normal cells and cancer cells. We have a long-standing interest in spindle orientation, centrosome position, and asymmetric cell division. We discovered mechanisms that link microtubules to polarized actin in yeast, and have recently defined analogous mechanisms in human cells. We study how centrosome amplification in cancer cells impacts cellular adhesion, cell migration, and tumor invasion. We have discovered new drug targets that kill cancer cells because of their centrosome amplification. We use biochemical and imaging approaches to understand these processes at a mechanistic level.

We are also interested in how aneuploidy (abnormal chomosome number) impacts tumor biology. We are particularly interested in the consequences of whole genome duplications, which recent genomic data suggest occur in nearly 40% of human cancers. We previously found that whole genome duplications resulting from cytokinesis failure can drive tumor development. We recently identified a mechanism by which errors in the segregation of intact chromosomes can cause DNA breaks, potentially resulting in cancer-causing mutations. These findings may explain the recently discovered phenomenon of chromothripsis, where a single chromosome or chromosome arm appears to undergo massive breakage and rearrangement. We are using single cell genome sequencing to define the impact of cell division errors on genome architecture.

Publications from Harvard Catalyst Profiles

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  • Leibowitz ML, Papathanasiou S, Doerfler PA, Blaine LJ, Sun L, Yao Y, Zhang CZ, Weiss MJ, Pellman D. Chromothripsis as an on-target consequence of CRISPR-Cas9 genome editing. Nat Genet 2021. PubMed
  • Wu RA, Pellman DS, Walter JC. The Ubiquitin Ligase TRAIP: Double-Edged Sword at the Replisome. Trends Cell Biol 2021; 31:75-85. PubMed
  • Papathanasiou S, Markoulaki S, Blaine LJ, Leibowitz ML, Zhang CZ, Jaenisch R, Pellman D. Whole chromosome loss and genomic instability in mouse embryos after CRISPR-Cas9 genome editing. Nat Commun 2021; 12:5855. PubMed
  • Ge JY, Shu S, Kwon M, Jovanović B, Murphy K, Gulvady A, Fassl A, Trinh A, Kuang Y, Heavey GA, Luoma A, Paweletz C, Thorner AR, Wucherpfennig KW, Qi J, Brown M, Sicinski P, McDonald TO, Pellman D, Michor F, Polyak K. Acquired resistance to combined BET and CDK4/6 inhibition in triple-negative breast cancer. Nat Commun 2020; 11:2350. PubMed
  • Umbreit NT, Zhang CZ, Lynch LD, Blaine LJ, Cheng AM, Tourdot R, Sun L, Almubarak HF, Judge K, Mitchell TJ, Spektor A, Pellman D. Mechanisms generating cancer genome complexity from a single cell division error. Science 2020. PubMed
  • Cortés-Ciriano I, Lee JJ, Xi R, Jain D, Jung YL, Yang L, Gordenin D, Klimczak LJ, Zhang CZ, Pellman DS, , Park PJ, . Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing. Nat Genet 2020; 52:331-341. PubMed
  • Deng L, Wu RA, Sonneville R, Kochenova OV, Labib K, Pellman D, Walter JC. Mitotic CDK Promotes Replisome Disassembly, Fork Breakage, and Complex DNA Rearrangements. Mol Cell 2019; 73:915-929.e6. PubMed
  • Jiao AL, Perales R, Umbreit NT, Haswell JR, Piper ME, Adams BD, Pellman D, Kennedy S, Slack FJ. Human Nuclear RNAi-Defective 2 (NRDE2) is an essential RNA splicing factor. RNA 2018. PubMed
  • Mowery CT, Reyes JM, Cabal-Hierro L, Higby KJ, Karlin KL, Wang JH, Kimmerling RJ, Cejas P, Lim K, Li H, Furusawa T, Long HW, Pellman D, Chapuy B, Bustin M, Manalis SR, Westbrook TF, Lin CY, Lane AA. Trisomy of a Down Syndrome Critical Region Globally Amplifies Transcription via HMGN1 Overexpression. Cell Rep 2018; 25:1898-1911.e5. PubMed
  • Witwicki RM, Ekram MB, Qiu X, Janiszewska M, Shu S, Kwon M, Trinh A, Frias E, Ramadan N, Hoffman G, Yu K, Xie Y, McAllister G, McDonald R, Golji J, Schlabach M, deWeck A, Keen N, Chan HM, Ruddy D, Rejtar T, Sovath S, Silver S, Sellers WR, Jagani Z, Hogarty MD, Roberts C, Brown M, Stegmaier K, Long H, Shivdasani RA, Pellman D, Polyak K. TRPS1 Is a Lineage-Specific Transcriptional Dependency in Breast Cancer. Cell Rep 2018; 25:1255-1267.e5. PubMed
  • Oser MG, Fonseca R, Chakraborty AA, Brough R, Spektor A, Jennings RB, Flaifel A, Novak JS, Gulati A, Buss E, Younger ST, McBrayer SK, Cowley GS, Bonal DM, Nguyen QD, Brulle-Soumare L, Taylor P, Cairo S, Ryan CJ, Pease EJ, Maratea K, Travers J, Root DE, Signoretti S, Pellman D, Ashton S, Lord CJ, Barry ST, Kaelin WG. Cells Lacking the RB1 Tumor Suppressor Gene are Hyperdependent on Aurora B Kinase for Survival. 2018. PubMed
  • Liu S, Kwon M, Mannino M, Yang N, Renda F, Khodjakov A, Pellman D. Nuclear envelope assembly defects link mitotic errors to chromothripsis. Nature 2018; 561:551-555. PubMed
  • Johnson WL, Xie KT, Kwon M, Liu S, Pellman D. How the Genome Folds, Divides, Lives, and Dies. Cold Spring Harb Symp Quant Biol 2018. PubMed
  • Marteil G, Guerrero A, Vieira AF, de Almeida BP, Machado P, Mendonça S, Mesquita M, Villarreal B, Fonseca I, Francia ME, Dores K, Martins NP, Jana SC, Tranfield EM, Barbosa-Morais NL, Paredes J, Pellman D, Godinho SA, Bettencourt-Dias M. Over-elongation of centrioles in cancer promotes centriole amplification and chromosome missegregation. Nat Commun 2018; 9:1258. PubMed
  • Spektor A, Umbreit NT, Pellman D. Cell Biology: When Your Own Chromosomes Act like Foreign DNA. Curr Biol 2017; 27:R1228-R1231. PubMed
  • Umbreit NT, Pellman D. Cancer biology: Genome jail-break triggers lockdown. Nature 2017. PubMed
  • Arellano-Santoyo H, Geyer EA, Stokasimov E, Chen GY, Su X, Hancock W, Rice LM, Pellman D. A Tubulin Binding Switch Underlies Kip3/Kinesin-8 Depolymerase Activity. Dev Cell 2017; 42:37-51.e8. PubMed
  • Li H, Mar BG, Zhang H, Puram RV, Vazquez F, Weir BA, Hahn WC, Ebert B, Pellman D. The EMT regulator ZEB2 is a novel dependency of human and murine acute myeloid leukemia. Blood 2017; 129:497-508. PubMed
  • Zhang CZ, Pellman D. From Mutational Mechanisms in Single Cells to Mutational Patterns in Cancer Genomes. Cold Spring Harb Symp Quant Biol 2016. PubMed
  • Leibowitz ML, Zhang CZ, Pellman D. Chromothripsis: A New Mechanism for Rapid Karyotype Evolution. Annu Rev Genet 2015; 49:183-211. PubMed
  • Kwon M, Bagonis M, Danuser G, Pellman D. Direct Microtubule-Binding by Myosin-10 Orients Centrosomes toward Retraction Fibers and Subcortical Actin Clouds. Dev Cell 2015; 34:323-37. PubMed
  • Zhang CZ, Spektor A, Cornils H, Francis JM, Jackson EK, Liu S, Meyerson M, Pellman D. Chromothripsis from DNA damage in micronuclei. Nature 2015; 522:179-84. PubMed
  • Selmecki AM, Maruvka YE, Richmond PA, Guillet M, Shoresh N, Sorenson AL, De S, Kishony R, Michor F, Dowell R, Pellman D. Polyploidy can drive rapid adaptation in yeast. Nature 2015; 519:349-52. PubMed
  • Varetti G, Pellman D, Gordon DJ. Aurea mediocritas: the importance of a balanced genome. Cold Spring Harb Perspect Biol 2014. PubMed
  • Ganem NJ, Cornils H, Chiu SY, O'Rourke KP, Arnaud J, Yimlamai D, Théry M, Camargo FD, Pellman D. Cytokinesis failure triggers hippo tumor suppressor pathway activation. Cell 2014; 158:833-48. PubMed
  • Godinho SA, Picone R, Burute M, Dagher R, Su Y, Leung CT, Polyak K, Brugge JS, Théry M, Pellman D. Oncogene-like induction of cellular invasion from centrosome amplification. Nature 2014. PubMed
  • Lane AA, Chapuy B, Lin CY, Tivey T, Li H, Townsend EC, van Bodegom D, Day TA, Wu SC, Liu H, Yoda A, Alexe G, Schinzel AC, Sullivan TJ, Malinge S, Taylor JE, Stegmaier K, Jaffe JD, Bustin M, te Kronnie G, Izraeli S, Harris MH, Stevenson KE, Neuberg D, Silverman LB, Sallan SE, Bradner JE, Hahn WC, Crispino JD, Pellman D, Weinstock DM. Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 Lys27 trimethylation. Nat Genet 2014. PubMed
  • Lee DH, Acharya SS, Kwon M, Drane P, Guan Y, Adelmant G, Kalev P, Shah J, Pellman D, Marto JA, Chowdhury D. Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks. Mol Cell 2014. PubMed
  • Su X, Arellano-Santoyo H, Portran D, Gaillard J, Vantard M, Thery M, Pellman D. Microtubule-sliding activity of a kinesin-8 promotes spindle assembly and spindle-length control. Nat Cell Biol 2013; 15:948-57. PubMed
  • Atkins BD, Yoshida S, Saito K, Wu CF, Lew DJ, Pellman D. Inhibition of Cdc42 during mitotic exit is required for cytokinesis. J Cell Biol 2013; 202:231-40. PubMed
  • Su X, Ohi R, Pellman D. Move in for the kill: motile microtubule regulators. Trends Cell Biol 2012; 22:567-75. PubMed
  • Buttery SM, Kono K, Stokasimov E, Pellman D. Regulation of the formin Bnr1 by septins anda MARK/Par1-family septin-associated kinase. Mol Biol Cell 2012; 23:4041-53. PubMed
  • Kono K, Saeki Y, Yoshida S, Tanaka K, Pellman D. Proteasomal degradation resolves competition between cell polarization and cellular wound healing. Cell 2012; 150:151-64. PubMed
  • Varetti G, Pellman D. "Two" much of a good thing: telomere damage-induced genome doubling drives tumorigenesis. Cancer Cell 2012; 21:712-4. PubMed
  • Carter SL, Cibulskis K, Helman E, McKenna A, Shen H, Zack T, Laird PW, Onofrio RC, Winckler W, Weir BA, Beroukhim R, Pellman D, Levine DA, Lander ES, Meyerson M, Getz G. Absolute quantification of somatic DNA alterations in human cancer. Nat Biotechnol 2012; 30:413-21. PubMed
  • Storchová Z, Becker JS, Talarek N, Kögelsberger S, Pellman D. Bub1, Sgo1, and Mps1 mediate a distinct pathway for chromosome biorientation in budding yeast. Mol Biol Cell 2011. PubMed
  • Meyerson M, Pellman D. Cancer genomes evolve by pulverizing single chromosomes. Cell 2011; 144:9-10. PubMed
  • Breuer M, Kolano A, Kwon M, Li CC, Tsai TF, Pellman D, Brunet S, Verlhac MH. HURP permits MTOC sorting for robust meiotic spindle bipolarity, similar to extra centrosome clustering in cancer cells. J Cell Biol 2010; 191:1251-60. PubMed
  • Vinciguerra P, Godinho SA, Parmar K, Pellman D, D'Andrea AD. Cytokinesis failure occurs in Fanconi anemia pathway-deficient murine and human bone marrow hematopoietic cells. J Clin Invest 2010; 120:3834-42. PubMed
  • Pellman D. David Pellman: Grasping the geometry of cancer. [Interviewed by Caitlin Sedwick]. J Cell Biol 2010; 190:4-5. PubMed
  • Kwiatkowski N, Jelluma N, Filippakopoulos P, Soundararajan M, Manak MS, Kwon M, Choi HG, Sim T, Deveraux QL, Rottmann S, Pellman D, Shah JV, Kops GJ, Knapp S, Gray NS. Small-molecule kinase inhibitors provide insight into Mps1 cell cycle function. Nat Chem Biol 2010; 6:359-68. PubMed
  • Tischfield MA, Baris HN, Wu C, Rudolph G, Van Maldergem L, He W, Chan WM, Andrews C, Demer JL, Robertson RL, Mackey DA, Ruddle JB, Bird TD, Gottlob I, Pieh C, Traboulsi EI, Pomeroy SL, Hunter DG, Soul JS, Newlin A, Sabol LJ, Doherty EJ, de Uzcátegui CE, de Uzcátegui N, Collins ML, Sener EC, Wabbels B, Hellebrand H, Meitinger T, de Berardinis T, Magli A, Schiavi C, Pastore-Trossello M, Koc F, Wong AM, Levin AV, Geraghty MT, Descartes M, Flaherty M, Jamieson RV, Møller HU, Meuthen I, Callen DF, Kerwin J, Lindsay S, Meindl A, Gupta ML, Pellman D, Engle EC. Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance. Cell 2010; 140:74-87. PubMed
  • Rhodes J, Amsterdam A, Sanda T, Moreau LA, McKenna K, Heinrichs S, Ganem NJ, Ho KW, Neuberg DS, Johnston A, Ahn Y, Kutok JL, Hromas R, Wray J, Lee C, Murphy C, Radtke I, Downing JR, Fleming MD, MacConaill LE, Amatruda JF, Gutierrez A, Galinsky I, Stone RM, Ross EA, Pellman DS, Kanki JP, Look AT. Emi1 maintains genomic integrity during zebrafish embryogenesis and cooperates with p53 in tumor suppression. Mol Cell Biol 2009; 29:5911-22. PubMed
  • Yoshida S, Bartolini S, Pellman D. Mechanisms for concentrating Rho1 during cytokinesis. Genes Dev 2009; 23:810-23. PubMed
  • Chandhok NS, Pellman D. A little CIN may cost a lot: revisiting aneuploidy and cancer. Curr Opin Genet Dev 2009; 19:74-81. PubMed
  • Atkins BD, Yoshida S, Pellman D. Symmetry breaking: scaffold plays matchmaker for polarity signaling proteins. Curr Biol 2008; 18:R1130-2. PubMed
  • Kwon M, Godinho SA, Chandhok NS, Ganem NJ, Azioune A, Thery M, Pellman D. Mechanisms to suppress multipolar divisions in cancer cells with extra centrosomes. Genes Dev 2008; 22:2189-203. PubMed
  • Austin KM, Gupta ML, Coats SA, Tulpule A, Mostoslavsky G, Balazs AB, Mulligan RC, Daley G, Pellman D, Shimamura A. Mitotic spindle destabilization and genomic instability in Shwachman-Diamond syndrome. J Clin Invest 2008; 118:1511-8. PubMed
  • Kono K, Nogami S, Abe M, Nishizawa M, Morishita S, Pellman D, Ohya Y. G1/S Cyclin-Dependent Kinase Regulates Small GTPase Rho1p through Phosphorylation of RhoGEF Tus1p in Saccharomyces cerevisiae. Mol Biol Cell 2008; 19:1763-71. PubMed
  • Yoshida S, Pellman D. Plugging the GAP between cell polarity and cell cycle. EMBO Rep 2008; 9:39-41. PubMed
  • Schüller U, Zhao Q, Godinho SA, Heine VM, Medema RH, Pellman D, Rowitch DH. Forkhead transcription factor FoxM1 regulates mitotic entry and prevents spindle defects in cerebellar granule neuron precursors. Mol Cell Biol 2007; 27:8259-70. PubMed
  • Ganem NJ, Pellman D. Limiting the proliferation of polyploid cells. Cell 2007; 131:437-40. PubMed
  • Ceol CJ, Pellman D, Zon LI. APC and colon cancer: two hits for one. Nat Med 2007; 13:1286-7. PubMed
  • Jallepalli PV, Pellman D. Cell biology. Aneuploidy in the balance. Science 2007; 317:904-5. PubMed
  • Buttery SM, Yoshida S, Pellman D. Yeast formins Bni1 and Bnr1 utilize different modes of cortical interaction during the assembly of actin cables. Mol Biol Cell 2007; 18:1826-38. PubMed
  • Ganem NJ, Storchova Z, Pellman D. Tetraploidy, aneuploidy and cancer. Curr Opin Genet Dev 2007; 17:157-62. PubMed
  • Pellman D. Cell biology: aneuploidy and cancer. Nature 2007; 446:38-9. PubMed
  • Storchová Z, Breneman A, Cande J, Dunn J, Burbank K, O'Toole E, Pellman D. Genome-wide genetic analysis of polyploidy in yeast. Nature 2006; 443:541-7. PubMed
  • Gupta ML, Carvalho P, Roof DM, Pellman D. Plus end-specific depolymerase activity of Kip3, a kinesin-8 protein, explains its role in positioning the yeast mitotic spindle. Nat Cell Biol 2006; 8:913-23. PubMed
  • Yoshida S, Kono K, Lowery DM, Bartolini S, Yaffe MB, Ohya Y, Pellman D. Polo-like kinase Cdc5 controls the local activation of Rho1 to promote cytokinesis. Science 2006; 313:108-11. PubMed
  • Kwon M, Godinho SA, Chandhok NS, Ganem NJ, Azioune A, Thery M, Pellman D. Mechanisms to suppress multipolar divisions in cancer cells with extra centrosomes. Genes Dev .
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