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: 10518845
• 负责人: Ken S Lau
• 金额: $ 173.04万
• 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/10518845
• 关键词: Address; 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; Coculture Techniques; 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; Epithelial Cells; Escherichia coli; Evolution; Exposure to; Foundations; Gastric Metaplasia; Generations; Genetic; Genotoxic Stress; Goals; Health system; Human; Immune; Immune system; Immunofluorescence Immunologic; Individual; Indolent; Intercept; Investigation; Joints; Knowledge; Lead; Lesion; Longitudinal cohort; Malignant Neoplasms; Manuscripts; Microbiology; Modeling; Molecular; Mucous Membrane; Nature; Organoids; Pathology; Pathway interactions; Perforation; Polypectomy; Polyps; Preventive; Process; Prospective Studies; Proteins; Reporting; Research; Research Personnel; Research Project Grants; Resources; Risk; Seminal; Shapes; Side; Specialized Program of Research Excellence; Surface; System; Systems Biology; Technology; Testing; Tissues; Translational Research; Woman; Work; adenoma; base; colon carcinogenesis; colorectal cancer prevention; cost effective; cytotoxic; design; exosome; extracellular vesicles; high risk; human data; human tissue; immunoregulation; 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; 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.

Vanderbilt TBEL中心组成了一个多学科的特定专家团队，以协作 研究结肠前癌进展的基本和翻译途径。我们关于 结肠前癌的两个亚型，腺瘤（ADS）和无链锯齿病变（SSLS）描绘了早期 肿瘤发生的起源是通过肿瘤细胞和免疫微环境调节和 微生物群。我们已经表明，SSL源自由胃中的胃化代理。 细胞毒性免疫微环境，而ADS是由干细胞衍生的Wnt激活在地穴上引起的 根据。在这个中心，我们将将对特定生物学机制的研究扩展到发展 这些预防性病变的轨迹成进展或懒惰。基本项目1调查 中性粒细胞-AD串扰的贡献，主要通过二肽酶1（DPEP1）在细胞表面并释放 在AD进展过程中，在小的细胞外囊泡中。翻译项​​目2调查人类 前瞻性研究，PKS+大肠杆菌的关联，诱导遗传毒性应激与前癌症 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调查了对抗原表现的调节干燥的稿件的获取 在肿瘤细胞和免疫系统之间共同进化的背景下，细胞毒性T细胞。联合分析 常见的结直肠前癌组织将有助于所有人的迭代和整合过程 项目。我们的TBEL中心提供了一种互补的融合，从还原主义和系统生物学方法到 研究与CRC的癌前肿瘤进展有关的关键因素。工作 将在人体组织上利用尖端技术，包括单细胞和空间转录组学，小 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GI先前建立的大量人类息肉资源 研究卓越研究专业计划和NCI Moonshot人类肿瘤网络将是 由TBEL中心的同一调查人员团队杠杆作用。此外，创新的共文化系统 每个项目都将采用每个项目，在该项目中，两极分化的前癌器官可以与密钥共同培养 从腔或基部暴露于肿瘤细胞的微环境元素。这项工作将告知 肿瘤发育轨迹的建模和确定将启用的进展机制 对有结直肠前的人的风险分层，预防精度和拦截的改善 癌症。