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（由申请人提供）：结直肠癌是美国癌症相关死亡的第三大原因，旨在表征人类结直肠癌基因组图谱的测序工作已发现 ARID1A 中存在高频率的失活突变，表明它是候选者。通过生成 ARID1A 失活的小鼠模型，我们证明 ARID1A 在结肠中具有真正的肿瘤抑制活性。 ARID1A 在小鼠体内的表达会导致侵袭性、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结直肠癌表型，并且代表了结肠癌模型的重大进步。在绝大多数人类结直肠癌中，通常是通过 APC 失活来实现的。虽然 APC 失活经常用于模拟结肠癌，但这些小鼠主要在小肠和结肠中形成腺瘤性息肉。因此，我们的研究结果表明 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建立的 ARID1A 的亚基不同的机制导致结肠癌的发展。 SWI/SNF 染色质重塑复合物，通过改变 DNA 对转录和共调控机制的可及性来调节基因表达。该复合物的亚基在癌症和生物信息学分析中广泛突变。最近的测序研究表明，20% 的人类癌症中 SWI/SNF 复合体发生突变，已知 SWI/SNF 亚基失活是癌症的起源驱动因素，与稳定的基因组和极低的基因突变率相关。强烈表明 SWI/SNF 复合物的突变通过表观遗传机制驱动癌症。然而，由于对这些癌症发病机制的了解有限，了解 SWI/SNF 复合物在驱动这些癌症中的作用已被证明是困难的。因此，ARID1A 失活驱动的结肠癌小鼠模型的建立为我们提供了一个独特的机会来研究 SWI/SNF 复合物的突变机制。通过我们的研究，我们将确定 ARID1A 缺失影响结肠上皮中 SWI/SNF 染色质重塑的机制，并确定表观遗传调控的途径。 SWI/SNF 复合物有助于 ARID1A 突变癌症的形成 为了检验 ARID1A 缺失通过表观遗传机制驱动结肠癌的假设，我们将利用我们的实验系统直接评估 ARID1A 缺失对结肠癌完整性的影响。这项研究将极大受益于我们与 Shivdasani 实验室（达纳法伯癌症研究所）的合作，该实验室在肠道发育和结肠癌生物学方面拥有专业知识。