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.
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.
