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 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). While the prospect of a driving role for BAF complex perturbation in human cancer is now vastly strengthened, mechanistic studies are limited by the fact that these mutation frequencies still occur in the context of numerous other mutations, therefore leaving open the possibility that other primary events are responsible for tumor initiation. To investigate the underlying mechanism, we initiated studies on 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. We show 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). Most importantly, we demonstrate the dynamic reversibility of this process;altering relative concentrations of wild-type SS18 results in reformation of wild-type BAF complexes, restoring normal complex architecture, localization over the genome, gene expression patterns, and halting SS cell proliferation. This biochemical mechanism represents the first to directly connect BAF complex subunit perturbation to a resultant oncogenic phenotype. In addition to the therapeutic opportunities which have emerged from these studies, harnessing the unique advantages of this specific disease context holds great promise to uncover the biochemical basis of BAF perturbation with broad relevance to a large number of human cancers. During the period of this award, we aim to accomplish the following key goals: (1) build approaches to the identification and characterization of a new class of probes which uniquely disrupt complex subunit pathways-of-assembly;(2) determine complex subunit and associated protein factor composition of oncogenic BAF complexes;(3) define the mechanistic basis of retargeting and altered remodeling activities of oncogenic BAF complexes at differentially poised chromatin landscapes. The proposed research builds upon my unique expertise at the border of biochemistry and chromatin regulation, and creates for a new synthesis of concepts and methodologies as novel strategies to target a broad range of human cancers.

Public Health Relevance

Recent whole genome sequencing efforts in human cancers have implicated aberrant chromatin remodeling as a significant, wide-spread player in oncogenesis, yet the biochemical mechanisms which result from such genomic changes remain unclear. Harnessing the power of disease settings in which the perturbation to a chromatin remodeling complex is the clear driving event affords a new opportunity for mechanistic discovery and therapeutic development. This proposal aims to uncover a new class of small molecule probes which target and modify the pathway-of-assembly of subunits within multimeric chromatin remodeling complexes, and to elucidate the structural, biochemical and genomic retargeting-based consequences of recurrent complex mutations.

National Institute of Health (NIH)
National Cancer Institute (NCI)
NIH Director’s New Innovator Awards (DP2)
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Special Emphasis Panel (ZRG1-MOSS-C (56))
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Knowlton, John R
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Dana-Farber Cancer Institute
United States
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Sandoval, Gabriel J; Pulice, John L; Pakula, Hubert et al. (2018) Binding of TMPRSS2-ERG to BAF Chromatin Remodeling Complexes Mediates Prostate Oncogenesis. Mol Cell 71:554-566.e7
Pan, Joshua; Meyers, Robin M; Michel, Brittany C et al. (2018) Interrogation of Mammalian Protein Complex Structure, Function, and Membership Using Genome-Scale Fitness Screens. Cell Syst 6:555-568.e7
St Pierre, Roodolph; Kadoch, Cigall (2017) Mammalian SWI/SNF complexes in cancer: emerging therapeutic opportunities. Curr Opin Genet Dev 42:56-67
Miller, Erik L; Hargreaves, Diana C; Kadoch, Cigall et al. (2017) TOP2 synergizes with BAF chromatin remodeling for both resolution and formation of facultative heterochromatin. Nat Struct Mol Biol 24:344-352
Kadoch, Cigall; Williams, Robert T; Calarco, Joseph P et al. (2017) Dynamics of BAF-Polycomb complex opposition on heterochromatin in normal and oncogenic states. Nat Genet 49:213-222
Nakayama, Robert T; Pulice, John L; Valencia, Alfredo M et al. (2017) SMARCB1 is required for widespread BAF complex-mediated activation of enhancers and bivalent promoters. Nat Genet 49:1613-1623
Stanton, Benjamin Z; Hodges, Courtney; Calarco, Joseph P et al. (2017) Smarca4 ATPase mutations disrupt direct eviction of PRC1 from chromatin. Nat Genet 49:282-288
Pulice, John L; Kadoch, Cigall (2016) Composition and Function of Mammalian SWI/SNF Chromatin Remodeling Complexes in Human Disease. Cold Spring Harb Symp Quant Biol 81:53-60
Kadoch, Cigall (2016) Lifting Up the HAT: Synthetic Lethal Screening Reveals a Novel Vulnerability at the CBP-p300 Axis. Cancer Discov 6:350-2