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: 10707105
• 负责人: Richard Brott Halberg
• 金额: $ 31.15万
• 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/10707105
• 关键词: APC gene; APC mutation; Acceleration; 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; 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; migration; mosaic; mouse model; mutant; neoplastic cell; prevent; progenitor; senescence; stem cells; success; transcriptomics; tumor; tumor heterogeneity; tumor progression; 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一直是美国和全世界的沉重负担，有超过193万 病例和2020年的95万人死亡。我们的研究旨在识别自主和非自治 早期腺瘤和周围结肠的属性，使腺瘤发展为恶性肿瘤。在 这个项目，我们模仿具有先前存在的突变克隆的底漆的结肠（AIM 1）或超负荷 衰老细胞（目标2）确定这些改变的状态是否增强了腺瘤的形成和 进展。可以用现代技术检测到这种属性，因此可以筛选个人 确定他们发展CRC的个人风险。我们建议腺瘤从底漆的结肠出现 可以从多个祖细胞中得出多含有多的来源。相互混合之间的相互作用 克隆可以以有利于腺瘤进展的方式改变参与克隆中的基因表达 （目标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 常见药物。因此，具有底漆结肠的个体，因此CRC的高风险可能是 识别，监视更频繁，并有可能治疗以防止癌症形成