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Dana Farber Boston Childrens Cancer and Blood Disorders Center Research
Hematology and Oncology Research
Pellman Laboratory Research

Research Overview

Our laboratory aims to understand normal cell division mechanisms and to discover cell division defects that are unique to cancer cell. 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 are particularly interested in how the microtubule and actin cytoskeletons interact and how cell cycle signals remodel these cytoskeletal systems. For example, we have recently uncovered a mechanism by which actin organization and the adhesive microenvironment of cells influence chromosome segregation. 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 have defined cytoskeletal mechanisms that control polarized cell growth, asymmetric cell division, and cytokinesis. We use biochemical and imaging approaches to understand these processes at a mechanistic level.

We are also interested in how aneuploidy (abnormal chromosome number) and polyploidy (increased sets of chromosomes) impact on tumor biology. We have developed new methods to generate human cells with specific cancer-associated trisomies and are studying how these trisomies impact tumorigenesis. We discovered that failure of cytokinesis, which doubles the number of chromosomes and centrosomes, promotes tumorigenesis, using a mouse breast cancer model. We recently identified a mechanism by which errors in mitosis cause DNA breaks. These findings may explain the recently discovered phenomenon of chromothripsis, where a single chromosome or chromosome arm appears to undergo massive breakage and rearrangement.

Research Background

David Pellman is the Margaret M. Dyson Professor of Pediatric Oncology at the Dana-Farber Cancer Institute and the Children’s Hospital Boston. He is also Professor of Cell Biology at Harvard Medical School and an Investigator of the Howard Hughes Medical Institute. Dr. Pellman received his MD from the University of Chicago, Pritzker School of Medicine. He completed an internship and residency at Dana-Farber Cancer Institute and Children's Hospital Boston. He was a postdoctoral fellow at the Whitehead Institute for Biomedical Research at the Massachusetts Institute of Technology.

He has received numerous awards including: the Graduate Student Mentoring Award from Harvard Medical School (1999), the Stohlman Scholar Award from the Leukemia & Lymphoma Society (2005); and the E. Mead Johnson Award from the Society for Pediatric Research (2006).

Publications

  1. TTF2 promotes replisome eviction from stalled forks in mitosis. bioRxiv. 2024 Nov 30. View Abstract
  2. Haplotype-resolved reconstruction and functional interrogation of cancer karyotypes. bioRxiv. 2024 Nov 26. View Abstract
  3. Chromosome breakage-replication/fusion enables rapid DNA amplification. bioRxiv. 2024 Aug 19. View Abstract
  4. 2D and 3D multiplexed subcellular profiling of nuclear instability in human cancer. bioRxiv. 2023 Nov 11. View Abstract
  5. Heritable transcriptional defects from aberrations of nuclear architecture. Nature. 2023 Jul; 619(7968):184-192. View Abstract
  6. Author Correction: Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing. Nat Genet. 2023 Jun; 55(6):1076. View Abstract
  7. ERa-associated translocations underlie oncogene amplifications in breast cancer. Nature. 2023 Jun; 618(7967):1024-1032. View Abstract
  8. Publisher Correction: Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing. Nat Genet. 2023 May; 55(5):893. View Abstract
  9. A tubule-sheet continuum model for the mechanism of nuclear envelope assembly. Dev Cell. 2023 05 22; 58(10):847-865.e10. View Abstract
  10. Breakage of cytoplasmic chromosomes by pathological DNA base excision repair. Nature. 2022 06; 606(7916):930-936. View Abstract
  11. Decoding complex patterns of oncogene amplification. Nat Genet. 2021 12; 53(12):1626-1627. View Abstract
  12. Whole chromosome loss and genomic instability in mouse embryos after CRISPR-Cas9 genome editing. Nat Commun. 2021 10 06; 12(1):5855. View Abstract
  13. Chromothripsis as an on-target consequence of CRISPR-Cas9 genome editing. Nat Genet. 2021 06; 53(6):895-905. View Abstract
  14. Angelika Amon (1967-2020). Nat Cell Biol. 2021 Jan; 23(1):1-2. View Abstract
  15. The Ubiquitin Ligase TRAIP: Double-Edged Sword at the Replisome. Trends Cell Biol. 2021 02; 31(2):75-85. View Abstract
  16. The coordination of nuclear envelope assembly and chromosome segregation in metazoans. Nucleus. 2020 12; 11(1):35-52. View Abstract
  17. Factors promoting nuclear envelope assembly independent of the canonical ESCRT pathway. J Cell Biol. 2020 06 01; 219(6). View Abstract
  18. Acquired resistance to combined BET and CDK4/6 inhibition in triple-negative breast cancer. Nat Commun. 2020 05 11; 11(1):2350. View Abstract
  19. Mechanisms generating cancer genome complexity from a single cell division error. Science. 2020 04 17; 368(6488). View Abstract
  20. Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing. Nat Genet. 2020 03; 52(3):331-341. View Abstract
  21. Mitotic CDK Promotes Replisome Disassembly, Fork Breakage, and Complex DNA Rearrangements. Mol Cell. 2019 03 07; 73(5):915-929.e6. View Abstract
  22. Human nuclear RNAi-defective 2 (NRDE2) is an essential RNA splicing factor. RNA. 2019 03; 25(3):352-363. View Abstract
  23. Trisomy of a Down Syndrome Critical Region Globally Amplifies Transcription via HMGN1 Overexpression. Cell Rep. 2018 11 13; 25(7):1898-1911.e5. View Abstract
  24. TRPS1 Is a Lineage-Specific Transcriptional Dependency in Breast Cancer. Cell Rep. 2018 10 30; 25(5):1255-1267.e5. View Abstract
  25. Cells Lacking the RB1 Tumor Suppressor Gene Are Hyperdependent on Aurora B Kinase for Survival. Cancer Discov. 2019 02; 9(2):230-247. View Abstract
  26. Nuclear envelope assembly defects link mitotic errors to chromothripsis. Nature. 2018 09; 561(7724):551-555. View Abstract
  27. How the Genome Folds, Divides, Lives, and Dies. Cold Spring Harb Symp Quant Biol. 2017; 82:349-360. View Abstract
  28. Over-elongation of centrioles in cancer promotes centriole amplification and chromosome missegregation. Nat Commun. 2018 03 28; 9(1):1258. View Abstract
  29. Cell Biology: When Your Own Chromosomes Act like Foreign DNA. Curr Biol. 2017 11 20; 27(22):R1228-R1231. View Abstract
  30. Cancer biology: Genome jail-break triggers lockdown. Nature. 2017 10 19; 550(7676):340-341. View Abstract
  31. A Tubulin Binding Switch Underlies Kip3/Kinesin-8 Depolymerase Activity. Dev Cell. 2017 07 10; 42(1):37-51.e8. View Abstract
  32. The EMT regulator ZEB2 is a novel dependency of human and murine acute myeloid leukemia. Blood. 2017 01 26; 129(4):497-508. View Abstract
  33. From Mutational Mechanisms in Single Cells to Mutational Patterns in Cancer Genomes. Cold Spring Harb Symp Quant Biol. 2015; 80:117-37. View Abstract
  34. Modeling the initiation of Ewing sarcoma tumorigenesis in differentiating human embryonic stem cells. Oncogene. 2016 06 16; 35(24):3092-102. View Abstract
  35. Chromothripsis: A New Mechanism for Rapid Karyotype Evolution. Annu Rev Genet. 2015; 49:183-211. View Abstract
  36. Direct Microtubule-Binding by Myosin-10 Orients Centrosomes toward Retraction Fibers and Subcortical Actin Clouds. Dev Cell. 2015 Aug 10; 34(3):323-37. View Abstract
  37. Chromothripsis from DNA damage in micronuclei. Nature. 2015 Jun 11; 522(7555):179-84. View Abstract
  38. Polyploidy can drive rapid adaptation in yeast. Nature. 2015 Mar 19; 519(7543):349-52. View Abstract
  39. Erratum: Parallel genome-scale loss of function screens in 216 cancer cell lines for the identification of context-specific genetic dependencies. Sci Data. 2014; 1:140044. View Abstract
  40. Parallel genome-scale loss of function screens in 216 cancer cell lines for the identification of context-specific genetic dependencies. Sci Data. 2014; 1:140035. View Abstract
  41. Aurea mediocritas: the importance of a balanced genome. Cold Spring Harb Perspect Biol. 2014 Sep 18; 6(11):a015842. View Abstract
  42. Causes and consequences of centrosome abnormalities in cancer. Philos Trans R Soc Lond B Biol Sci. 2014 Sep 05; 369(1650). View Abstract
  43. Cytokinesis failure triggers hippo tumor suppressor pathway activation. Cell. 2014 Aug 14; 158(4):833-848. View Abstract
  44. Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 Lys27 trimethylation. Nat Genet. 2014 Jun; 46(6):618-23. View Abstract
  45. Oncogene-like induction of cellular invasion from centrosome amplification. Nature. 2014 Jun 05; 510(7503):167-71. View Abstract
  46. Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks. Mol Cell. 2014 May 08; 54(3):512-25. View Abstract
  47. Chromothripsis and beyond: rapid genome evolution from complex chromosomal rearrangements. Genes Dev. 2013 Dec 01; 27(23):2513-30. View Abstract
  48. Inhibition of Cdc42 during mitotic exit is required for cytokinesis. J Cell Biol. 2013 Jul 22; 202(2):231-40. View Abstract
  49. Microtubule-sliding activity of a kinesin-8 promotes spindle assembly and spindle-length control. Nat Cell Biol. 2013 Aug; 15(8):948-57. View Abstract
  50. Linking abnormal mitosis to the acquisition of DNA damage. J Cell Biol. 2012 Dec 10; 199(6):871-81. View Abstract
  51. Move in for the kill: motile microtubule regulators. Trends Cell Biol. 2012 Nov; 22(11):567-75. View Abstract
  52. Regulation of the formin Bnr1 by septins anda MARK/Par1-family septin-associated kinase. Mol Biol Cell. 2012 Oct; 23(20):4041-53. View Abstract
  53. Proteasomal degradation resolves competition between cell polarization and cellular wound healing. Cell. 2012 Jul 06; 150(1):151-64. View Abstract
  54. "Two" much of a good thing: telomere damage-induced genome doubling drives tumorigenesis. Cancer Cell. 2012 Jun 12; 21(6):712-4. View Abstract
  55. Absolute quantification of somatic DNA alterations in human cancer. Nat Biotechnol. 2012 May; 30(5):413-21. View Abstract
  56. Causes and consequences of aneuploidy in cancer. Nat Rev Genet. 2012 Jan 24; 13(3):189-203. View Abstract
  57. DNA breaks and chromosome pulverization from errors in mitosis. Nature. 2012 Jan 18; 482(7383):53-8. View Abstract
  58. Mechanisms underlying the dual-mode regulation of microtubule dynamics by Kip3/kinesin-8. Mol Cell. 2011 Sep 02; 43(5):751-63. View Abstract
  59. Centrosomes and cilia in human disease. Trends Genet. 2011 Aug; 27(8):307-15. View Abstract
  60. Bub1, Sgo1, and Mps1 mediate a distinct pathway for chromosome biorientation in budding yeast. Mol Biol Cell. 2011 May; 22(9):1473-85. View Abstract
  61. Cancer genomes evolve by pulverizing single chromosomes. Cell. 2011 Jan 07; 144(1):9-10. View Abstract
  62. HURP permits MTOC sorting for robust meiotic spindle bipolarity, similar to extra centrosome clustering in cancer cells. J Cell Biol. 2010 Dec 27; 191(7):1251-60. View Abstract
  63. Cytokinesis failure occurs in Fanconi anemia pathway-deficient murine and human bone marrow hematopoietic cells. J Clin Invest. 2010 Nov; 120(11):3834-42. View Abstract
  64. David Pellman: Grasping the geometry of cancer. Interviewed by Caitlin Sedwick. J Cell Biol. 2010 Jul 12; 190(1):4-5. View Abstract
  65. Small-molecule kinase inhibitors provide insight into Mps1 cell cycle function. Nat Chem Biol. 2010 May; 6(5):359-68. View Abstract
  66. Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance. Cell. 2010 Jan 08; 140(1):74-87. View Abstract
  67. Emi1 maintains genomic integrity during zebrafish embryogenesis and cooperates with p53 in tumor suppression. Mol Cell Biol. 2009 Nov; 29(21):5911-22. View Abstract
  68. A mechanism linking extra centrosomes to chromosomal instability. Nature. 2009 Jul 09; 460(7252):278-82. View Abstract
  69. Centrosomes and cancer: how cancer cells divide with too many centrosomes. Cancer Metastasis Rev. 2009 Jun; 28(1-2):85-98. View Abstract
  70. Mechanisms for concentrating Rho1 during cytokinesis. Genes Dev. 2009 Apr 01; 23(7):810-23. View Abstract
  71. A little CIN may cost a lot: revisiting aneuploidy and cancer. Curr Opin Genet Dev. 2009 Feb; 19(1):74-81. View Abstract
  72. Symmetry breaking: scaffold plays matchmaker for polarity signaling proteins. Curr Biol. 2008 Dec 23; 18(24):R1130-2. View Abstract
  73. Mechanisms to suppress multipolar divisions in cancer cells with extra centrosomes. Genes Dev. 2008 Aug 15; 22(16):2189-203. View Abstract
  74. Mitotic spindle destabilization and genomic instability in Shwachman-Diamond syndrome. J Clin Invest. 2008 Apr; 118(4):1511-8. View Abstract
  75. G1/S cyclin-dependent kinase regulates small GTPase Rho1p through phosphorylation of RhoGEF Tus1p in Saccharomyces cerevisiae. Mol Biol Cell. 2008 Apr; 19(4):1763-71. View Abstract
  76. Plugging the GAP between cell polarity and cell cycle. EMBO Rep. 2008 Jan; 9(1):39-41. View Abstract
  77. Limiting the proliferation of polyploid cells. Cell. 2007 Nov 02; 131(3):437-40. View Abstract
  78. APC and colon cancer: two hits for one. Nat Med. 2007 Nov; 13(11):1286-7. View Abstract
  79. Forkhead transcription factor FoxM1 regulates mitotic entry and prevents spindle defects in cerebellar granule neuron precursors. Mol Cell Biol. 2007 Dec; 27(23):8259-70. View Abstract
  80. Cell biology. Aneuploidy in the balance. Science. 2007 Aug 17; 317(5840):904-5. View Abstract
  81. Yeast formins Bni1 and Bnr1 utilize different modes of cortical interaction during the assembly of actin cables. Mol Biol Cell. 2007 May; 18(5):1826-38. View Abstract
  82. Cell biology: aneuploidy and cancer. Nature. 2007 Mar 01; 446(7131):38-9. View Abstract
  83. Tetraploidy, aneuploidy and cancer. Curr Opin Genet Dev. 2007 Apr; 17(2):157-62. View Abstract
  84. Genome-wide genetic analysis of polyploidy in yeast. Nature. 2006 Oct 05; 443(7111):541-7. View Abstract
  85. Plus end-specific depolymerase activity of Kip3, a kinesin-8 protein, explains its role in positioning the yeast mitotic spindle. Nat Cell Biol. 2006 Sep; 8(9):913-23. View Abstract
  86. Polo-like kinase Cdc5 controls the local activation of Rho1 to promote cytokinesis. Science. 2006 Jul 07; 313(5783):108-11. View Abstract
  87. Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature. 2005 Oct 13; 437(7061):1043-7. View Abstract
  88. MEN signaling: daughter bound pole must escape her mother to be fully active. Dev Cell. 2005 Aug; 9(2):168-70. View Abstract
  89. Mitotic spindle: laser microsurgery in yeast cells. Curr Biol. 2004 Sep 21; 14(18):R748-50. View Abstract
  90. Defects arising from whole-genome duplications in Saccharomyces cerevisiae. Genetics. 2004 Jul; 167(3):1109-21. View Abstract
  91. Cell cycle control of kinesin-mediated transport of Bik1 (CLIP-170) regulates microtubule stability and dynein activation. Dev Cell. 2004 Jun; 6(6):815-29. View Abstract
  92. Crystal structures of a Formin Homology-2 domain reveal a tethered dimer architecture. Cell. 2004 Mar 05; 116(5):711-23. View Abstract
  93. The differential roles of budding yeast Tem1p, Cdc15p, and Bub2p protein dynamics in mitotic exit. Mol Biol Cell. 2004 Apr; 15(4):1519-32. View Abstract
  94. From polyploidy to aneuploidy, genome instability and cancer. Nat Rev Mol Cell Biol. 2004 Jan; 5(1):45-54. View Abstract
  95. A conserved mechanism for Bni1- and mDia1-induced actin assembly and dual regulation of Bni1 by Bud6 and profilin. Mol Biol Cell. 2004 Feb; 15(2):896-907. View Abstract
  96. Surfing on microtubule ends. Trends Cell Biol. 2003 May; 13(5):229-37. View Abstract
  97. Processing, localization, and requirement of human separase for normal anaphase progression. Proc Natl Acad Sci U S A. 2003 Apr 15; 100(8):4574-9. View Abstract
  98. Determinants of S. cerevisiae dynein localization and activation: implications for the mechanism of spindle positioning. Curr Biol. 2003 Mar 04; 13(5):364-72. View Abstract
  99. The molecular function of Ase1p: evidence for a MAP-dependent midzone-specific spindle matrix. Microtubule-associated proteins. J Cell Biol. 2003 Feb 17; 160(4):517-28. View Abstract
  100. Formin-2, polyploidy, hypofertility and positioning of the meiotic spindle in mouse oocytes. Nat Cell Biol. 2002 Dec; 4(12):921-8. View Abstract
  101. An actin nucleation mechanism mediated by Bni1 and profilin. Nat Cell Biol. 2002 Aug; 4(8):626-31. View Abstract
  102. Analysis of the size and shape of protein complexes from yeast. Methods Enzymol. 2002; 351:150-68. View Abstract
  103. Yeast formins regulate cell polarity by controlling the assembly of actin cables. Nat Cell Biol. 2002 Jan; 4(1):42-50. View Abstract
  104. Polyploids require Bik1 for kinetochore-microtubule attachment. J Cell Biol. 2001 Dec 24; 155(7):1173-84. View Abstract
  105. The social life of actin and microtubules: interaction versus cooperation. Curr Opin Microbiol. 2001 Dec; 4(6):696-702. View Abstract
  106. A two-tiered mechanism by which Cdc42 controls the localization and activation of an Arp2/3-activating motor complex in yeast. J Cell Biol. 2001 Oct 15; 155(2):261-70. View Abstract
  107. Separase anxiety: dissolving the sister bond and more. Nat Cell Biol. 2001 Sep; 3(9):E207-9. View Abstract
  108. Activity of the APC(Cdh1) form of the anaphase-promoting complex persists until S phase and prevents the premature expression of Cdc20p. J Cell Biol. 2001 Jul 09; 154(1):85-94. View Abstract
  109. Microtubule "plus-end-tracking proteins": The end is just the beginning. Cell. 2001 May 18; 105(4):421-4. View Abstract
  110. Cancer. A CINtillating new job for the APC tumor suppressor. Science. 2001 Mar 30; 291(5513):2555-6. View Abstract
  111. Rvb1p and Rvb2p are essential components of a chromatin remodeling complex that regulates transcription of over 5% of yeast genes. J Biol Chem. 2001 May 11; 276(19):16279-88. View Abstract
  112. Search, capture and signal: games microtubules and centrosomes play. J Cell Sci. 2001 Jan; 114(Pt 2):247-55. View Abstract
  113. Positioning of the mitotic spindle by a cortical-microtubule capture mechanism. Science. 2000 Mar 24; 287(5461):2260-2. View Abstract
  114. Yeast Bim1p promotes the G1-specific dynamics of microtubules. J Cell Biol. 1999 May 31; 145(5):993-1007. View Abstract
  115. The APC-associated protein EB1 associates with components of the dynactin complex and cytoplasmic dynein intermediate chain. Curr Biol. 1999 Apr 22; 9(8):425-8. View Abstract
  116. Control of mitotic spindle position by the Saccharomyces cerevisiae formin Bni1p. J Cell Biol. 1999 Mar 08; 144(5):947-61. View Abstract
  117. The adenomatous polyposis coli-binding protein EB1 is associated with cytoplasmic and spindle microtubules. Proc Natl Acad Sci U S A. 1998 Sep 01; 95(18):10596-601. View Abstract
  118. Deubiquitinating enzymes: a new class of biological regulators. Crit Rev Biochem Mol Biol. 1998; 33(5):337-52. View Abstract
  119. Kinesin-related KIP3 of Saccharomyces cerevisiae is required for a distinct step in nuclear migration. J Cell Biol. 1997 Sep 08; 138(5):1023-40. View Abstract
  120. APC-mediated proteolysis of Ase1 and the morphogenesis of the mitotic spindle. Science. 1997 Feb 28; 275(5304):1311-4. View Abstract
  121. Two microtubule-associated proteins required for anaphase spindle movement in Saccharomyces cerevisiae. J Cell Biol. 1995 Sep; 130(6):1373-85. View Abstract
  122. The yeast nuclear import receptor is required for mitosis. Proc Natl Acad Sci U S A. 1995 Aug 15; 92(17):7647-51. View Abstract
  123. TATA-dependent and TATA-independent transcription at the HIS4 gene of yeast. Nature. 1990 Nov 01; 348(6296):82-5. View Abstract
  124. 78-kilodalton glucose-regulated protein is induced in Rous sarcoma virus-transformed cells independently of glucose deprivation. Mol Cell Biol. 1988 Jul; 8(7):2675-80. View Abstract
  125. Fine structural mapping of a critical NH2-terminal region of p60src. Proc Natl Acad Sci U S A. 1985 Mar; 82(6):1623-7. View Abstract
  126. An N-terminal peptide from p60src can direct myristylation and plasma membrane localization when fused to heterologous proteins. Nature. 1985 Mar 28-Apr 3; 314(6009):374-7. View Abstract
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