Photo of Cigall Kadoch,  PhD

Cigall Kadoch, PhD

Dana-Farber Cancer Institute

Dana-Farber Cancer Institute


cigall_kadoch@dfci.harvard.edu

Cigall Kadoch, PhD

Dana-Farber Cancer Institute

EDUCATIONAL TITLES

  • Assistant Professor, Pediatrics, Harvard Medical School
  • Assistant Professor, Pediatric Oncology, Dana-Farber Cancer Institute
  • Principal Investigator, Pediatric Oncology, Dana-Farber Cancer Institute
  • Institute Member, Chemical Biology, Broad Institute of MIT and Harvard

DF/HCC PROGRAM AFFILIATION

Research Abstract

Recent whole-genome sequencing studies of human cancers have heralded the discovery of several new, surprising classes of genes not previously known to play causal roles in cancer. One of the most significant findings unveiled in these genomic studies is the high mutation frequency in genes involved in epigenomic and chromatin biology-based processes. The most frequent and wide-spread among them are mutations in the genes encoding subunits of the mSWI/SNF (BAF) ATP-dependent chromatin remodeling complexes, which we recently determined to be broadly recurrent in >20% of all human cancers (Kadoch et al, Nature Genetics 2013). To investigate the underlying mechanism, we have studied a rare, genomically well-defined cancer type, human synovial sarcoma (SS) in which 100% of tumors have a precise translocation involving a specific subunit, SS18, indicating that the translocation is the initiating oncogenic event. The utility of this disease setting has provided us with a powerful foundation toward understanding the oncogenic mechanisms directed by altered chromatin remodeling complexes. We showed that perturbation via the SS18-SSX fusion usurps BAF complex protein subunit composition, and that this restructuring mistargets complexes to specific oncogenic loci to drive proliferation (Kadoch and Crabtree, Cell 2013). Excitingly, we demonstrate the dynamic reversibility of this process in this setting and extend these approaches and findings to other cancer types with BAF complex mutations.

The central focus of our laboratory is to understand BAF complex pathway-of-assembly, to determine the complex subunit and associated protein factor composition of oncogenic BAF complexes, and to define the mechanistic basis of locus-specific and genome-wide retargeting. These key goals build upon our unique expertise at the border of biochemistry and chromatin regulation, and create for a new synthesis of concepts and methodologies as novel strategies to target a broad range of human cancers.

Publications

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  • Pan J, McKenzie ZM, D'Avino AR, Mashtalir N, Lareau CA, St Pierre R, Wang L, Shilatifard A, Kadoch C. The ATPase module of mammalian SWI/SNF family complexes mediates subcomplex identity and catalytic activity-independent genomic targeting. Nat Genet 2019; 51:618-626. PubMed
  • Valencia AM, Kadoch C. Chromatin regulatory mechanisms and therapeutic opportunities in cancer. Nat Cell Biol 2019. PubMed
  • Menotti M, Ambrogio C, Cheong TC, Pighi C, Mota I, Cassel SH, Compagno M, Wang Q, Dall'Olio R, Minero VG, Poggio T, Sharma GG, Patrucco E, Mastini C, Choudhari R, Pich A, Zamo A, Piva R, Giliani S, Mologni L, Collings CK, Kadoch C, Gambacorti-Passerini C, Notarangelo LD, Anton IM, Voena C, Chiarle R. Wiskott-Aldrich syndrome protein (WASP) is a tumor suppressor in T cell lymphoma. Nat Med 2018. PubMed
  • Michel BC, D'Avino AR, Cassel SH, Mashtalir N, McKenzie ZM, McBride MJ, Valencia AM, Zhou Q, Bocker M, Soares LMM, Pan J, Remillard DI, Lareau CA, Zullow HJ, Fortoul N, Gray NS, Bradner JE, Chan HM, Kadoch C. A non-canonical SWI/SNF complex is a synthetic lethal target in cancers driven by BAF complex perturbation. Nat Cell Biol 2018; 20:1410-1420. PubMed
  • Mashtalir N, D'Avino AR, Michel BC, Luo J, Pan J, Otto JE, Zullow HJ, McKenzie ZM, Kubiak RL, St Pierre R, Valencia AM, Poynter SJ, Cassel SH, Ranish JA, Kadoch C. Modular Organization and Assembly of SWI/SNF Family Chromatin Remodeling Complexes. Cell 2018; 175:1272-1288.e20. PubMed
  • Zhang H, Pandey S, Travers M, Sun H, Morton G, Madzo J, Chung W, Khowsathit J, Perez-Leal O, Barrero CA, Merali C, Okamoto Y, Sato T, Pan J, Garriga J, Bhanu NV, Simithy J, Patel B, Huang J, Raynal NJ, Garcia BA, Jacobson MA, Kadoch C, Merali S, Zhang Y, Childers W, Abou-Gharbia M, Karanicolas J, Baylin SB, Zahnow CA, Jelinek J, GraƱa X, Issa JJ. Targeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer. Cell 2018; 175:1244-1258.e26. PubMed
  • Sandoval GJ, Pulice JL, Pakula H, Schenone M, Takeda DY, Pop M, Boulay G, Williamson KE, McBride MJ, Pan J, St Pierre R, Hartman E, Garraway LA, Carr SA, Rivera MN, Li Z, Ronco L, Hahn WC, Kadoch C. Binding of TMPRSS2-ERG to BAF Chromatin Remodeling Complexes Mediates Prostate Oncogenesis. Mol Cell 2018; 71:554-566.e7. PubMed
  • McBride MJ, Pulice JL, Beird HC, Ingram DR, D'Avino AR, Shern JF, Charville GW, Hornick JL, Nakayama RT, Garcia-Rivera EM, Araujo DM, Wang WL, Tsai JW, Yeagley M, Wagner AJ, Futreal PA, Khan J, Lazar AJ, Kadoch C. The SS18-SSX Fusion Oncoprotein Hijacks BAF Complex Targeting and Function to Drive Synovial Sarcoma. Cancer Cell 2018; 33:1128-1141.e7. PubMed
  • Pan J, Meyers RM, Michel BC, Mashtalir N, Sizemore AE, Wells JN, Cassel SH, Vazquez F, Weir BA, Hahn WC, Marsh JA, Tsherniak A, Kadoch C. Interrogation of Mammalian Protein Complex Structure, Function, and Membership Using Genome-Scale Fitness Screens. Cell Syst 2018; 6:555-568.e7. PubMed
  • McBride MJ, Kadoch C. Disruption of mammalian SWI/SNF and polycomb complexes in human sarcomas: mechanisms and therapeutic opportunities. J Pathol 2018; 244:638-649. PubMed
  • Otto JE, Kadoch C. A Two-Faced mSWI/SNF Subunit: Dual Roles for ARID1A in Tumor Suppression and Oncogenicity in the Liver. Cancer Cell 2017; 32:542-543. PubMed
  • Nakayama RT, Pulice JL, Valencia AM, McBride MJ, McKenzie ZM, Gillespie MA, Ku WL, Teng M, Cui K, Williams RT, Cassel SH, Qing H, Widmer CJ, Demetri GD, Irizarry RA, Zhao K, Ranish JA, Kadoch C. SMARCB1 is required for widespread BAF complex-mediated activation of enhancers and bivalent promoters. Nat Genet 2017. PubMed
  • Boulay G, Sandoval GJ, Riggi N, Iyer S, Buisson R, Naigles B, Awad ME, Rengarajan S, Volorio A, McBride MJ, Broye LC, Zou L, Stamenkovic I, Kadoch C, Rivera MN. Cancer-Specific Retargeting of BAF Complexes by a Prion-like Domain. Cell 2017; 171:163-178.e19. PubMed
  • Michel BC, Kadoch C. A SMARCD2-containing mSWI/SNF complex is required for granulopoiesis. Nat Genet 2017; 49:655-657. PubMed
  • Pierre RS, Kadoch C. Mammalian SWI/SNF complexes in cancer: emerging therapeutic opportunities. Curr Opin Genet Dev 2017; 42:56-67. PubMed
  • Miller EL, Hargreaves DC, Kadoch C, Chang CY, Calarco JP, Hodges C, Buenrostro JD, Cui K, Greenleaf WJ, Zhao K, Crabtree GR. TOP2 synergizes with BAF chromatin remodeling for both resolution and formation of facultative heterochromatin. Nat Struct Mol Biol 2017; 24:344-352. PubMed
  • Stanton BZ, Hodges C, Calarco JP, Braun SM, Ku WL, Kadoch C, Zhao K, Crabtree GR. Smarca4 ATPase mutations disrupt direct eviction of PRC1 from chromatin. Nat Genet 2016; 49:282-288. PubMed
  • Kadoch C, Williams RT, Calarco JP, Miller EL, Weber CM, Braun SM, Pulice JL, Chory EJ, Crabtree GR. Dynamics of BAF-Polycomb complex opposition on heterochromatin in normal and oncogenic states. Nat Genet 2016; 49:213-222. PubMed
  • Poynter ST, Kadoch C. Polycomb and trithorax opposition in development and disease. Wiley Interdiscip Rev Dev Biol 2016. PubMed
  • Kadoch C. Lifting Up the HAT: Synthetic Lethal Screening Reveals a Novel Vulnerability at the CBP-p300 Axis. 2016; 6:350-2. PubMed
  • Kadoch C, Copeland RA, Keilhack H. PRC2 and SWI/SNF Chromatin Remodeling Complexes in Health and Disease. Biochemistry 2016; 55:1600-14. PubMed
  • Pulice JL, Kadoch C. Composition and Function of Mammalian SWI/SNF Chromatin Remodeling Complexes in Human Disease. Cold Spring Harb Symp Quant Biol 2017; 81:53-60. PubMed
  • Kadoch C, Crabtree GR. Mammalian SWI/SNF chromatin remodeling complexes and cancer: Mechanistic insights gained from human genomics. Sci Adv 2015; 1:e1500447. PubMed
  • Kadoch C, Li J, Wong VS, Chen L, Cha S, Munster P, Lowell CA, Shuman MA, Rubenstein JL. Complement activation and intraventricular rituximab distribution in recurrent central nervous system lymphoma. Clin Cancer Res 2014. PubMed
  • Rubenstein JL, Wong VS, Kadoch C, Gao HX, Barajas R, Chen L, Josephson SA, Scott B, Douglas V, Maiti M, Kaplan LD, Treseler PA, Cha S, Hwang JH, Cinque P, Cyster JG, Lowell C. CXCL13 plus interleukin 10 is highly specific for the diagnosis of CNS lymphoma. Blood 2013; 121:4740-8. PubMed
  • Kadoch C, Hargreaves DC, Hodges C, Elias L, Ho L, Ranish J, Crabtree GR. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat Genet 2013; 45:592-601. PubMed
  • Kadoch C, Crabtree GR. Reversible disruption of mSWI/SNF (BAF) complexes by the SS18-SSX oncogenic fusion in synovial sarcoma. Cell 2013; 153:71-85. PubMed
  • Rubenstein JL, Li J, Chen L, Advani R, Drappatz J, Gerstner E, Batchelor T, Krouwer H, Hwang J, Auerback G, Kadoch C, Lowell C, Munster P, Cha S, Shuman MA, Damon LE. Multicenter phase 1 trial of intraventricular immunochemotherapy in recurrent CNS lymphoma. Blood 2013; 121:745-51. PubMed
  • Algazi AP, Kadoch C, Rubenstein JL. Biology and treatment of primary central nervous system lymphoma. 2009; 6:587-97. PubMed
  • Kadoch C, Dinca EB, Voicu R, Chen L, Nguyen D, Parikh S, Karrim J, Shuman MA, Lowell CA, Treseler PA, James CD, Rubenstein JL. Pathologic correlates of primary central nervous system lymphoma defined in an orthotopic xenograft model. Clin Cancer Res 2009; 15:1989-97. PubMed
  • Rubenstein JL,Shen A,Batchelor TT,Kadoch C,Treseler P,Shuman MA. Differential gene expression in central nervous system lymphoma. Blood 2009; 113:266-7; author reply 267-8. PubMed
  • Roy S, Josephson SA, Fridlyand J, Karch J, Kadoch C, Karrim J, Damon L, Treseler P, Kunwar S, Shuman MA, Jones T, Becker CH, Schulman H, Rubenstein JL. Protein biomarker identification in the CSF of patients with CNS lymphoma. J Clin Oncol 2007; 26:96-105. PubMed
  • Kadoch C, Treseler P, Rubenstein JL. Molecular pathogenesis of primary central nervous system lymphoma. Neurosurg Focus 2006; 21:E1. PubMed
  • Kadoch C, D'Amico AV, Matthews RH. When prostate brachytherapy fails: a case report and discussion. Oncologist 2005; 10:799-805. PubMed
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