Elucidating the Role of SMAD4 in Colorectal Cancer

阐明 SMAD4 在结直肠癌中的作用

• 批准号: 9977419
• 负责人: Kevin Tong
• 金额: $ 12.03万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977419
• 关键词: Address; Award; BRAF gene; Binding; Binding Sites; Bioinformatics; Biological Models; Cancer Etiology; Carcinoma; Cell Nucleus; Cessation of life; ChIP-seq; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; DNA Binding; DNA Sequence Alteration; Data; Development; 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; 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; clinically relevant; colon cancer cell line; colon cancer patients; colon cancer progression; combat; effective therapy; epigenomics; gain of function; genetic profiling; in vivo; insight; men; mouse model; mutant; novel; outcome forecast; 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.

项目概要/摘要 结肠癌是美国癌症相关死亡的第二大原因，也是最严重的癌症之一。 实体瘤的特征在于其常见的基因突变。然而，知识差距存在 对这些癌症下游基因谱的基本了解。例如，肿瘤抑制剂 大约 57% 的结肠肿瘤中基因 SMAD4 发生突变，并且与不良预后相关 但对其在结肠癌中的分子机制仍知之甚少。此外， 而约 70% 的结肠癌遵循典型的 WNT 驱动的腺瘤到癌途径，大约 20% 的人遵循“锯齿状肿瘤途径”——通常由功能获得性 BRAF 突变驱动，并且情况最差 结肠癌的预后。该提案的主要目标将集中于阐明 结肠癌中的肿瘤抑制因子 SMAD4。假设 SMAD4 起着关键的转录作用 WNT 通路的调节作用，是锯齿状肿瘤通路的关键调节因子。这 基本原理基于初步研究，该研究揭示：1) SMAD4 与基因组的调控区域结合 也与 ß-连环蛋白结合 - β-连环蛋白是最常见突变信号通路的转录效应子 结肠癌，WNT通路； 2) SMAD4 缺失与 BRAF 激活相结合，可以触发 小鼠中锯齿状肿瘤的形成速度最快为 1 个月。目标 1 将使用表观基因组方法来绘制 SMAD4 与 ß-catenin 在 DNA 结合水平上的相互作用 - 详细描述了这些相互作用的第一个交叉点 结肠癌基因组上的通路。 Aim 2 将使用新的小鼠模型来确定 SMAD4 如何 抑制锯齿状癌症从增生性病变到不典型增生的转变。目标 3 将使用最先进的 艺术肿瘤类器官模型系统，以确定 SMAD4 如何抑制锯齿状癌症转移。目标 目的是测试以下假设：1) SMAD4 通过重定向 ß-catenin 直接调节 WNT 信号通路 与 RUNX3 协同作用于肿瘤抑制基因靶点，从而影响癌症的发展，以及 2) SMAD4 抑制锯齿状肿瘤进展所需的关键信号通路 转移。拟议的研究具有重要意义，因为它们将确定常见的监管目标 突变的肿瘤抑制基因，为研究不足但更致命的结肠提供了新的视角 癌症肿瘤类型。这些研究将对癌症研究领域产生广泛影响，并将揭示新的 目标是识别和治疗锯齿状肿瘤患者。在博士的共同指导下。迈克尔·韦尔齐和 罗纳德·哈特 (Ronald Hart)，该提案的培训计划将使我为向独立过渡做好准备：1) 继续 增强我的表观基因组学技能，2）开发新颖的模型系统来解决结肠中的关键问题 癌症领域，3）强化建立和维持我自己的独立研究计划所需的技能。 罗格斯大学遗传学系对于我的博士后来说是一个出色的机构 培训，当我向独立过渡时，我将从环境中受益匪浅。