BBS Faculty Member - Cigall Kadoch

Cigall Kadoch

Department of Pediatric Oncology
Department of Biological Chemistry and Molecular Pharmacology

Dana Farber Cancer Institute
Dana Building, Room 620
450 Brookline Avenue
Boston, MA 02115
Tel: 617-632-3789
Email: cigall_kadoch@dfci.harvard.edu



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.



Last Update: 9/4/2014



Publications

Kadoch C and Crabtree GR. Reversible disruption of mSWI/SNF (BAF) complexes by the SS18-SSX oncogenic fusion in synovial sarcoma. Cell 2013 Mar 28; 153(1): 71-85.

See also: Svejstrup JQ. Synovial sarcoma mechanisms: a series of unfortunate events.
Cell 2013 Mar 28; 153(1): 11-12.

Kadoch C, Hargreaves DC, Hodges C, Elias LA, Ho L, Ranish J, and Crabtree GR. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nature Genetics 2013 Jun;45(6):592-601.



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