Features of the early adenoma and adjacent colon that drive progression: the role of mutation burden in normal tissue, senescent cells, and tumor clonal architecture

驱动进展的早期腺瘤和邻近结肠的特征：突变负荷在正常组织、衰老细胞和肿瘤克隆结构中的作用

• 批准号: 10519075
• 负责人: Richard Brott Halberg
• 金额: $ 39.03万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10519075
• 关键词: APC gene; APC mutation; Affect; Architecture; Cancerous; Carcinoma; Cells; Cessation of life; Chemopreventive Agent; Collection; Colon; DNA sequencing; Development; Epithelial Cells; Event; Fibroblasts; Gene Expression; Genes; Genetic; Individual; KRAS2 gene; Label; Malignant Neoplasms; Modernization; Molecular; Mosaicism; Mus; Mutation; Normal tissue morphology; PIK3CA gene; Paracrine Communication; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Proliferating; Regulatory Pathway; Risk; Role; Signal Transduction; Solid; Stromal Cells; TP53 gene; Technology; Testing; Tissues; Tumor Suppressor Genes; United States; adenoma; cancer risk; design; gut microbiome; high risk; innovation; mouse model; mutant; neoplastic cell; prevent; progenitor; senescence; stem cells; transcriptomics; tumor; tumor heterogeneity; tumorigenic

PROJECT SUMMARY CRC persists as a heavy burden in the United States and throughout the world with over 1.93 million new cases and 0.95 million deaths in 2020. Our study is designed to identify autonomous and non-autonomous attributes of the early adenoma and the surrounding colon that drive adenoma progression to malignancy. In this project, we mimic in mice a primed colon with pre-existing mutant clones (Aim 1) or overloaded with senescent cells (Aim 2) to determine whether these altered states enhance adenoma formation and progression. Such attributes can be detected with modern technology, so individuals could be screened to determine their personal risk of developing CRC. We propose that adenomas emerging from a primed colon can have a multi-ancestral origin being derived from multiple progenitors. Interactions among intermingled clones could alter gene expression in the participating clones in a manner that favors adenoma progression (Aim 3). Such interactions could potentially be disrupted with new chemopreventive agents or repurposed common drugs. Thus, individuals having a primed colon and consequently at a high risk of CRC could be identified, surveilled more frequently, and potentially treated to prevent cancers from forming

项目摘要 CRC在美国和全世界仍然是一个沉重的负担， 2020年新增病例95万例，死亡95万例。我们的研究旨在区分自主和非自主 早期腺瘤和周围结肠的属性促使腺瘤进展为恶性肿瘤。在 在这个项目中，我们用预先存在的突变克隆（Aim 1）或过载的 衰老细胞（目的2），以确定这些改变的状态是否会促进腺瘤形成， 进展这些属性可以用现代技术检测出来，因此可以对个人进行筛选， 确定他们发展CRC的个人风险。我们认为，从启动的结肠中出现的腺瘤 可以具有来自多个祖先的多祖先起源。相互作用 克隆可以改变参与克隆的基因表达， (Aim 3）。这种相互作用可能会被新的化学预防剂破坏或重新利用 普通毒品因此，具有引发的结肠并因此处于CRC高风险的个体可以被治疗。 更频繁地进行识别、监测，并可能进行治疗以预防癌症的形成