Shaping of the Microenvironment in Colonic Pre-Cancer by Epithelia and Microbiota

上皮细胞和微生物群对结肠癌前期微环境的塑造

• 批准号: 10697365
• 负责人: Ken S Lau
• 金额: $ 165.78万
• 依托单位: VANDERBILT 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: 2022-09-15 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10697365
• 关键词: Antigen Presentation; Atlases; Basic Science; Big Bang Cosmology; Binding; Biological; Biological Models; Biological Process; Biological Sciences; Biometry; Cancer Biology; Cancer Etiology; Carcinoma; Cell Communication; Cell Line; Cell surface; Cells; Cellular biology; Cessation of life; Chemoprevention; Clinical Data; Clonal Expansion; Coculture Techniques; Collaborations; Colon; Colonic Neoplasms; Colonoscopy; Colorectal; Colorectal Adenoma; Computational Biology; Computational algorithm; Cytotoxic T-Lymphocytes; Data; Data Analyses; Detection; Development; Dipeptidases; Dipeptides; Disease model; Elements; Epidemiology; Epithelial Cells; Epithelium; Escherichia coli; Evolution; Exposure to; Gastric Metaplasia; Generations; Genetic; Genotoxic Stress; Health system; Human; Immune; Immune system; Immunofluorescence Immunologic; Individual; Indolent; Investigation; Joints; Knowledge; Lead; Lesion; Longitudinal cohort; Malignant Neoplasms; Manuscripts; Microbiology; Modeling; Molecular; Mucous Membrane; Mutagens; Nature; Organoids; Pathology; Pathway interactions; Perforation; Polypectomy; Polyps; Preventive; Process; Prospective Studies; Proteins; Reporting; Research; Research Personnel; Research Project Grants; Resources; Risk; Science; Seminal; Shapes; Side; Specialized Program of Research Excellence; Surface; System; Systems Biology; Technology; Testing; Tissues; Translational Research; United States; Woman; Work; adenoma; base; colon carcinogenesis; colorectal cancer prevention; cost effective; cytotoxic; design; exosome; extracellular vesicles; high risk; human data; human tissue; immunoregulation; improved; in vitro Model; in vivo Model; individualized prevention; innovation; iterative design; men; microbial; microbiota; molecular phenotype; multidisciplinary; multiplexed imaging; neoplastic cell; neutrophil; next generation; novel; polyketide synthase; premalignant; pressure; prevent; programs; protein biomarkers; risk stratification; single-cell RNA sequencing; stem cells; stemness; transcriptomics; translational goal; tumor; tumor heterogeneity; tumor microenvironment; tumor-immune system interactions; tumorigenesis

The Vanderbilt TBEL Center assembles a multi-disciplinary team of field-specific experts to collaboratively investigate the basic and translational pathways of colonic pre-cancer progression. Our foundational work on two subtypes of colonic pre-cancers, adenomas (ADs) and sessile serrated lesions (SSLs), depicts the early origins of tumorigenesis that are shaped by modulation of the immune microenvironment via neoplastic cells and the microbiota. We have shown that SSLs originate from gastric metaplasia arising from the mucosal surface in a cytotoxic immune microenvironment, whereas ADs arise from stem cell-derived WNT activation at the crypt base. In this center, we will extend our investigation of specific biological mechanisms towards the developmental trajectories of these pre-malignant lesions into progression or indolence. Basic Project 1 investigates the contribution of neutrophil-AD crosstalk, largely via dipeptidase 1 (DPEP1) both at the cell surface and released in small extracellular vesicles, in the course of AD progression. Translational Project 2 investigates, in human prospective studies, the association of pks+ Escherichia coli that induces genotoxic stress with pre-cancer progression, as well as colon epithelial cell and mucosa mechanisms that may contribute to a polyp-promoting microenvironment. Basic Project 3 investigates acquisition of stemness in modulating antigen presentation to cytotoxic T cells in the context of co-evolution between neoplastic cells and the immune system. Joint analysis of common colorectal pre-cancer tissues will facilitate an ongoing process of iteration and integration across all projects. Our TBEL Center offers a complementary blend, from reductionist and systems biology approaches, to investigate critical factors involved in the progression of pre-cancerous tumors of the colon to CRC. The work will utilize cutting-edge technologies on human tissues, including single-cell and spatial transcriptomics, small extracellular vesicle profiling, multiplex imaging, longitudinal data analysis, and next-generation computational algorithms. In addition, substantial human polyp resources previously established by the Vanderbilt GI Specialized Programs of Research Excellence and the NCI Moonshot Human Tumor Atlas Network will be leveraged by the same team of investigators in the TBEL Center. In addition, an innovative co-culture system will be employed by each project, where polarizing pre-cancer organoids can be co-cultured with key microenvironment elements exposed to neoplastic cells from the luminal or basal side. This work will inform the modeling of tumor development trajectories and identify mechanisms of progression that will enable improvements in risk stratification, precision prevention, and interception for individuals with colorectal pre- cancers.

范德比尔特 TBEL 中心组建了一支由特定领域专家组成的多学科团队， 研究结肠癌前期进展的基本和转化途径。我们的基础工作是 结肠癌前期的两种亚型，腺瘤（AD）和无蒂锯齿状病变（SSL），描述了早期 肿瘤发生的起源是通过肿瘤细胞调节免疫微环境而形成的 微生物群。我们已经证明 SSL 起源于粘膜表面的胃化生 细胞毒性免疫微环境，而 AD 是由干细胞衍生的隐窝 WNT 激活引起的 根据。在该中心，我们将对特定生物机制的研究扩展到发育 这些癌前病变进展或惰性的轨迹。基本项目 1 调查 中性粒细胞-AD 串扰的贡献，主要是通过细胞表面和释放的二肽酶 1 (DPEP1) 在 AD 进展过程中，存在于小细胞外囊泡中。转化项目 2 调查人类 前瞻性研究，诱导基因毒性应激的 pks+ 大肠杆菌与癌前病变的关系 进展以及可能有助于息肉促进的结肠上皮细胞和粘膜机制 微环境。基本项目 3 研究在调节抗原呈递过程中获得干性 肿瘤细胞与免疫系统共同进化背景下的细胞毒性T细胞。联合分析 常见结直肠癌前组织的研究将促进所有结直肠癌前组织持续迭代和整合的过程 项目。我们的 TBEL 中心提供互补的融合，从还原论和系统生物学方法，到 研究结肠癌前肿瘤进展为结直肠癌的关键因素。工作 将利用人体组织的尖端技术，包括单细胞和空间转录组学、小型 细胞外囊泡分析、多重成像、纵向数据分析和下一代计算 算法。此外，范德比尔特地理研究所先前建立的大量人类息肉资源 卓越研究专门计划和 NCI Moonshot 人类肿瘤图谱网络将 由 TBEL 中心的同一研究团队利用。此外，创新的共培养系统 将被每个项目采用，其中极化癌前类器官可以与关键的共培养 从管腔或基底侧暴露于肿瘤细胞的微环境元素。这项工作将告知 肿瘤发展轨迹的建模并确定进展机制，这将使 改善结直肠癌前期患者的风险分层、精准预防和拦截 癌症。