Defining the changing microbiome composition and host-microbe mechanistic effects following Apc inactivation during colorectal cancer pathogenesis

定义结直肠癌发病过程中 Apc 失活后微生物组组成的变化和宿主微生物机制效应

• 批准号: 10750676
• 负责人: Lindsey Dzierozynski
• 金额: $ 4.77万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-16 至 2026-09-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750676
• 关键词: 16S ribosomal RNA sequencing; APC gene; APC mutation; Acceleration; Adherence; Area; Attention; Automobile Driving; Benign; Biology; Cancer Etiology; Carcinoma; Cessation of life; Characteristics; Chronology; Colitis; Colon; Colorectal Cancer; Colorectal Neoplasms; DNA Damage; DNA Sequence Alteration; Data; Development; Diagnosis; Disease; Early identification; Environment; Epithelial Cells; Epithelium; Event; Future; Gene Expression Regulation; Genetic; Germ-Free; Goals; Habitats; Hand; Histopathology; Human; Individual; Inflammatory Bowel Diseases; Laboratory Finding; Lesion; Malignant Neoplasms; Measures; Metabolic Pathway; Microbe; Microbiology; Modeling; Mucositis; Mucous Membrane; Mus; Mutate; Mutation; Pathogenesis; Pathogenicity; Patient Care; Prevention; Proliferating; Research; Spatial Distribution; Testing; Therapeutic; Time; Tissues; Tumor Suppressor Genes; Woman; adenoma; anticancer research; cancer risk; cancer therapy; carcinogenesis; colon cancer patients; colon microbiota; colon tumorigenesis; colorectal cancer prevention; colorectal cancer progression; driver mutation; dysbiosis; fecal microbiome; host microbiome; innovation; insight; member; men; metabolomics; microbial; microbial colonization; microbial composition; microbiome; microbiome composition; microbiota; mortality; mouse model; novel; novel strategies; pathogen; permissiveness; time use; transcriptome sequencing; transcriptomics; tumor; tumor microbiome; tumor microenvironment; tumor progression; tumorigenesis; tumorigenic

Project Summary Globally, colorectal cancer (CRC) is the second leading cause of cancer-related deaths in men and women and is projected to increase by 70% in the next 20 years. One of the earliest initiating events of CRC is mutation of adenomatous polyposis coli (APC), a tumor suppressor gene. This mutation initiates the gradual progression from normal proliferating colon epithelial cells (CECs) to dysplastic lesions, to the eventual formation of tumors, known as adenomas. Somatic APC mutations occur in >80% of sporadic CRCs. Growing evidence demonstrates that factors within the local microenvironment can significantly influence cancer risk and onset. One key characteristic of the colon adenomatous environment is an imbalanced microbiome. Disruption in the makeup of these microbiota, known as dysbiosis, is related to many diseases, including colitis, inflammatory bowel disease, and CRC. While dysbiosis contributes to promoting adenoma progression and CRC, whether APC mutation triggers changes in the local microenvironment to facilitate tumor progression and microbiome dysbiosis remains largely unknown. Using an inducible murine model of CEC Apc truncation, our lab found that Apc inactivation and subsequent colon tumorigenesis results in microbiome dysbiosis and outgrowth of pathogenic species, further, associated with increased bacterial mucosal adherence. This proposal aims to define the timing and mechanisms by which the early microbiome changes following Apc inactivation. We hypothesize that Apc loss alters the microenvironment to cause early loss of commensal species and provides a habitat for pathogenic outgrowth and pro-carcinogenesis. We will test our hypothesis through the following aims. Aim 1: Defining the effects of Apc inactivation on the composition, spatial/temporal dynamics, and tumorigenic potential of the host microbiome. Using 16S rRNA amplicon sequencing and microbiology, I will identify early microbiome changes following Apc loss during gradual colon tumorigenesis and will determine if this differs by colon region. I will use germ-free models to evaluate if the changing microbiome is sufficient to induce colon tumorigenesis. Aim 2: Identifying the mechanism(s) by which Apc inactivation contributes to microbiome dysbiosis and the expansion of pathogenic species. I will utilize transcriptomics and metabolomics to examine changes in metabolic pathways and gene regulation in association with changes in microbiome composition and timing of Apc inactivation. This research will provide novel insights into the events occurring upon Apc mutation and the crosstalk between mutated CECs and the local microbiome.

项目摘要 在全球范围内，大肠癌（CRC）是男性和女性与癌症相关死亡的第二大原因 预计未来20年将增加70％。 CRC最早的事件之一是 腺瘤性息肉病（APC）的突变，肿瘤抑制基因。该突变启动了渐进 从正常增殖的结肠上皮细胞（CEC）到发育不良病变的进展，最终 肿瘤的形成，称为腺瘤。 > 80％的零星CRC中发生了体细胞APC突变。生长 有证据表明，局部微环境内的因素可以显着影响癌症的风险 和发作。结肠腺瘤环境的一个关键特征是一个不平衡的微生物组。 这些菌群的构成中断，称为营养不良，与许多疾病有关，包括 结肠炎，炎症性肠病和CRC。虽然营养不良有助于促进腺瘤进展 和CRC，APC突变是否触发局部微环境的变化以促进肿瘤进展 和微生物组营养不良仍然很大未知。使用CEC APC截断的诱导鼠模型， 我们的实验室发现，APC失活和随后的结肠肿瘤发生导致微生物组营养不良和 致病物种的生长，与细菌粘膜粘附增加有关。这 提案旨在定义APC后早期微生物组发生变化的时间和机制 失活。我们假设APC损失改变了微环境，以引起共生的早期损失 物种并为致病性产物和促癌作用提供了栖息地。我们将检验我们的假设 通过以下目标。目标1：定义APC失活对组成，空间/时间的影响 宿主微生物组的动力学和致瘤潜力。使用16S rRNA扩增子测序和 微生物学，我将在逐渐结肠肿瘤发生后APC丢失后确定早期的微生物组变化 并将确定这与结肠区域是否不同。我将使用无菌模型来评估是否发生变化 微生物组足以诱导结肠肿瘤发生。目标2：确定APC的机制 失活有助于微生物组营养不良和致病物种的扩张。我会利用 转录组学和代谢组学检查代谢途径的变化和基因调节的变化 与微生物组组成的变化和APC失活的时机的变化有关。这项研究将提供 对APC突变和突变CEC之间的串扰发生的事件的新颖见解 局部微生物组。