Colorectal cancer is the third leading cause of cancer-related death in the United States. Sequencing efforts to characterize the genomic landscapes of human colorectal cancers have identified high frequencies of inactivating mutations in ARID1A, implicating it as a candidate genetic driver. By generating a mouse model of ARID1A inactivation, we have demonstrated that ARID1A has bona fide tumor suppressor activity in the colon. Conditional, tissue non-specific knockout of ARID1A in mice leads to the development of aggressive, invasive colon adenocarcinomas. Notably, this mouse model reflects the human colorectal cancer phenotype more accurately than any existing mouse model, and represents a significant advance in colon cancer modeling. The Wnt signaling pathway is deregulated in the vast majority of human colorectal cancers, often through inactivation of APC. While APC-inactivation is frequently used to model colon cancer, these mice primarily develop adenomatous polyps in the small intestine and rarely progress to carcinomas. Our findings thus demonstrate that ARID1A has a critical tumor suppressor role in the colon, and that its inactivation leads to the development of colon cancers via a mechanism that is distinct from previously established genetic models. ARID1A is a subunit of the SWI/SNF chromatin remodeling complex, which regulates gene expression by altering the accessibility of DNA to transcriptional and co-regulatory machinery. Subunits of the complex are broadly mutated in cancers, and bioinformatics analyses of sequencing studies have recently demonstrated that the SWI/SNF complex is mutated in 20% of all human cancers. Cancers in which inactivation of SWI/SNF subunits is known to be the originating driver are associated with stable genomes and extremely low rates of genetic mutations, strongly suggesting that mutation of SWI/SNF complexes drives cancer via an epigenetic mechanism. However, understanding the role of SWI/SNF complexes in driving these cancers has proven difficult due to the limited knowledge of the pathogenesis of these rare cancers (including cell type of origin), and the lack of adequate model systems. The establishment of our ARID1A inactivation-driven colon cancer mouse model thus presents us with a unique opportunity to investigate the mechanism by which mutation of the SWI/SNF complex can drive oncogenesis in a well-defined system. Through our investigation, we will define the mechanism by which ARID1A loss affects SWI/SNF chromatin remodeling in the colonic epithelium, and will identify pathways epigenetically regulated by SWI/SNF complexes that contribute to the formation of ARID1A-mutant cancers. To test our hypothesis that ARID1A loss drives colon cancer via an epigenetic mechanism, we will make use of our experimental systems to directly evaluate any effects of ARID1A loss on the integrity of the genome. This investigation will greatly benefit from our collaboration with the Shivdasani Lab (Dana-Farber Cancer Institute), which has expertise in intestinal development and colon cancer biology.
Subunits of SWI/SNF chromatin remodeling complexes are mutated in 20% of all human cancers, but the mechanisms by which they drive cancer are poorly understood. The subunit ARID1A is frequently mutated in human colon cancers, and we have shown that its inactivation in mice leads to the formation of aggressive colon tumors. We will use our newly established mouse model to test our hypothesis that ARID1A functions as a tumor suppressor in an epigenetic capacity via its contribution to SWI/SNF chromatin remodeling.
| Mathur, Radhika; Alver, Burak H; San Roman, Adrianna K et al. (2017) ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice. Nat Genet 49:296-302 |
