Investigating the role of ARID1A inactivation in colon cancer pathogenesis

研究 ARID1A 失活在结肠癌发病机制中的作用

• 批准号: 8978656
• 负责人: Radhika Mathur
• 金额: $ 3.54万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8978656
• 关键词: Adenomatous Polyps; Affect; Automobile Driving; Binding; Bioinformatics; Biological Models; Cancer Biology; Cancer Etiology; Cancer Model; Carcinoma; Cell Line; Cells; Cessation of life; Chromatin; Chromatin Remodeling Factor; Collaborations; Colon; Colon Adenocarcinoma; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Complex; DNA; DNA Sequence Alteration; Dana-Farber Cancer Institute; Data; Development; Enhancers; Epigenetic Process; Epithelial Cells; Epithelium; Frequencies; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Models; Genetic Transcription; Genome; Genomics; HCT116 Cells; Human; In Vitro; Intestines; Investigation; Knock-out; Knowledge; Malignant Neoplasms; Mediating; Modeling; Morphology; Mus; Mutate; Mutation; Pathogenesis; Pathway interactions; Phenotype; Recurrence; Regulatory Element; Residual state; Role; Sequence Analysis; Signal Pathway; Small Intestines; System; Testing; Tissues; Transcriptional Regulation; Tumor Suppressor Proteins; United States; Variant; beta catenin; cell type; chromatin remodeling; colon cancer cell line; defined contribution; design; genome integrity; insight; mouse model; mutant; novel; public health relevance; tumorigenesis

 DESCRIPTION (provided by applicant): 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.

 描述（由适用提供）：大肠癌是美国与癌症相关死亡的第三主要原因。表征人类结直肠癌基因组景观的测序努力已经确定了ARID1A中灭活突变的高频，暗示它是候选遗传驱动器。通过生成抗抗活化的小鼠模型，我们证明了ARID1A具有真正的肿瘤抑制剂活性。小鼠ARID1A的条件性组织非特异性敲除导致侵略性，侵袭性结肠腺癌的发展。值得注意的是，该小鼠模型比任何现有的小鼠模型都更准确地反映了人类大肠癌表型，并且代表了结肠癌建模的重大进展。 Wnt信号通路通常通过APC失活而在绝大多数人的结直肠癌中受到失调。虽然APC灭活经常用于建模结肠癌，但这些小鼠主要在小肠中发展出腺瘤息肉，并且很少发展为癌。因此，我们的发现表明，ARID1A在结肠中具有关键的肿瘤抑制作用，并且其失活通过与先前确定的遗传模型不同的机制导致结肠癌的发展。 ARID1A是SWI/SNF染色质重塑复合物的亚基，它通过改变DNA对转录和共调控机制的可访问性来调节基因表达。该复合物的亚基在癌症中被广泛突变，测序研究的生物信息学分析最近表明，在所有人类癌症中，SWI/SNF复合物在20％中被突变。已知SWI/SNF亚基灭活的癌症是起源驱动因素与稳定的基因组和遗传突变速率极低相关的癌症，强烈表明SWI/SNF复合物的突变通过表观遗传机制驱动癌症。但是，由于对这些罕见癌症的发病机理的了解有限（包括原始的细胞类型）以及缺乏适当的模型系统，因此很难了解SWI/SNF复合物在驱动这些癌症中的作用。因此，建立我们的ARID1A灭活驱动的结肠癌小鼠模型为我们提供了独特的机会，以研究SWI/SNF复合物突变可以在明确定义的系统中驱动肿瘤发生的机制。通过我们的研究，我们将定义ARID1A损失影响结肠上皮中SWI/SNF染色质重塑的机制，并将确定由SWI/SNF复合物表观遗传调节的途径，这些途径有助于ARID1A-突变剂的形成。为了检验我们的假设，即ARID1A损失通过表观遗传机制驱动结肠癌，我们将利用我们的实验系统直接评估ARID1A损失对基因组完整性的任何影响。这项投资将大大受益于我们与Shivdasani Lab（Dana-Farber Cancer Institute）的合作，该实验室在肠道发展和结肠癌生物学方面具有专业知识。