Elucidating the Role of SMAD4 in Colorectal Cancer

阐明 SMAD4 在结直肠癌中的作用

• 批准号: 10614758
• 负责人: Kevin Tong
• 金额: $ 24.9万
• 依托单位: HACKENSACK UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614758
• 关键词: Address; Award; BRAF gene; Binding; Binding Sites; Bioinformatics; Biological Models; Cancer Etiology; Carcinoma; Cell Nucleus; Cessation of life; ChIP-seq; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; DNA Binding; DNA Sequence Alteration; Data; Development; Disseminated Malignant Neoplasm; Dysplasia; Environment; Foundations; Future; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Transcription; Genome; Goals; Hyperplasia; Institution; Kinetics; Knowledge; Laboratory Research; Lesion; MADH4 gene; Malignant Neoplasms; Maps; Measurement; Measures; Mentorship; Modeling; Molecular; Molecular Target; Mus; Mutate; Mutation; Neoplasm Metastasis; Nucleic Acid Regulatory Sequences; Oncogenic; Organoids; Pathology; Pathway interactions; Patients; Phase; Play; Prognosis; RUNX3 gene; Research; Resources; Role; Science; Signal Pathway; Solid Neoplasm; System; Testing; Tissues; Training; Transforming Growth Factor beta; Translating; Transplantation; Tumor Suppressor Genes; Tumor Suppressor Proteins; Tumor Tissue; United States; Universities; WNT Signaling Pathway; Woman; adenoma; anticancer research; base; beta catenin; cancer genome; cancer therapy; cancer type; clinically relevant; colon cancer cell line; colon cancer patients; colon cancer progression; effective therapy; epigenomics; gain of function; in vivo; insight; men; mouse model; mutant; novel; post-doctoral training; programs; role model; screening; skills; therapeutic target; tool; transcription factor; tumor; tumor progression; tumorigenesis

Project Summary/Abstract Colon cancer is the 2nd-leading cause of cancer-related deaths in the United States and is one of the best- characterized solid tumors in terms of its common genetic mutations. However, knowledge gaps exist in the basic understanding of these cancers downstream of their genetic profile. For instance, the tumor-suppressor gene SMAD4 is mutated in approximately 57% of all colon tumors, and is associated with poor prognosis in patients, yet there is still little understanding of its molecular mechanisms in colon cancer. Additionally, while ~70% of colon cancers follow the typical WNT-driven adenoma-to-carcinoma pathway, approximately 20% follow the “serrated tumor pathway”- often driven by gain-of-function BRAF mutations and have the worst prognosis of colon cancers. The proposal’s main objective will focus on elucidating the mechanistic role of the tumor suppressor SMAD4 in colon cancers. The hypothesis is that SMAD4 plays a critical transcriptional regulatory role in regulating the WNT pathway and is a key regulator in the serrated tumor pathway. The rationale is based on preliminary studies that reveal: 1) that SMAD4 binds to regulatory regions of the genome also bound by ß-catenin – the transcriptional effector of the most commonly mutated signaling pathway in colon cancer, the WNT pathway; and 2) SMAD4 loss, when combined with activation of BRAF, can trigger serrated tumor formation as rapidly as 1 month in mice. Aim 1 will use epigenomic approaches to map the interaction of SMAD4 with ß-catenin at the level of DNA-binding - detailing the first intersection of these pathways on the colon cancer genome. Aim 2 will use new mouse models to determine how SMAD4 suppresses the serrated cancer transition from hyperplastic lesions to dysplasias. Aim 3 will use state-of-the- art tumor organoid model systems to determine how SMAD4 suppresses serrated cancer metastasis. The goal is to test the hypotheses that 1) SMAD4 directly regulates the WNT-signaling pathway by redirecting ß-catenin to tumor-suppressive gene targets in coordination with RUNX3, thus impacting cancer development, and 2) that SMAD4 suppresses key signaling pathways that are required for serrated tumor progression and metastasis. The proposed studies are significant in that they will identify the regulatory targets of a commonly mutated tumor-suppressor gene and present a new perspective on an understudied, but more deadly, colon cancer tumor type. These studies would have broad impacts in the cancer research field, and will reveal new targets to identify and treat patients with serrated tumors. With the co-mentorship of Drs. Michael Verzi and Ronald Hart, this proposal's training plan will prepare me for a transition to independence by 1) continuing to enhance my epigenomics skillset, 2) develop novel model systems to address critical questions in the colon cancer field, and 3) fortify the skills required to establish and maintain my own independent research program. The Department of Genetics at Rutgers University has been an outstanding institution for my postdoctoral training, and I will benefit greatly from the environment as I transition towards independence.

项目摘要/摘要 结肠癌是美国与癌症相关死亡死亡的第二个领先原因，是最好的 实体瘤的OTS OTS OTS OUMON遗传突变。 对这些癌症的基本理解，例如它们的遗传特征。 基因SMAD4在所有Collon肿瘤的大约57％中都静音，并且在预后不良的孔隙率不佳。 患者对结肠癌的分子机制几乎没有理解。 约有70％的结肠癌遵循典型的WNT驱动腺瘤至 - 卡道瘤途径，大约 20％遵循“锯齿状肿瘤途径”，通常是由功能良好的BRAF变异驱动的，并且具有质量 结肠癌的预后。 肿瘤抑制smad4在结肠癌中。 调节WNT途径的调节作用是锯齿状肿瘤途径中的关键调节剂 基本原理是基于预先研究的研究：1）SMAD4与基因组的调节区域结合 也由ß-catenin绑定 - 最常见的静音信号通路的转录有效 结肠癌，WNT途径； 在小鼠1中，锯齿状的肿瘤形成迅速。 Smad4与ß-catenin在DNA结合限制的水平上的相互作用的第一个相交 结肠癌基因组上的途径2。 抑制了从增生到发育不良的锯齿状癌症过渡。 ART肿瘤器官模型系统确定SMAD4如何抑制锯齿状的癌症转移 是测试假设1）SMAD4通过重定向ß -catenin直接调节Wnt信号途径 与肿瘤抑制基因靶标与Runx3协调，从而影响癌症的发展，而2） Smad4抑制了锯齿状肿瘤进展所需的关键信号通路和 转移。 柔和的肿瘤抑制剂基因，并在一个被察觉但更致命的结肠上提出了新的观点 癌症肿瘤类型。 鉴定和治疗脑部肿瘤的患者 罗纳德·哈特（Ronald Hart 增强我的表观基因组学技能，2）开发新型模型系统来解决结肠中的关键问题 癌症领域和3）强化建立和维护自己的独立研究计划所需的技能。 罗格斯大学的遗传学系已成为我的博士后的杰出机构 培训，当我向独立过渡时，我将从环境中受益。