Integrative Single-Cell Atlas of Host and Microenvironment in Colorectal Neoplastic Transformation

结直肠肿瘤转化中宿主和微环境的综合单细胞图谱

• 批准号: 10380489
• 负责人: Robert J. Coffey
• 金额: $ 21.18万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380489
• 关键词: Address; Adenocarcinoma; Adverse event; Atlases; Cancer Etiology; Carcinoma; Cells; Cessation of life; Chemoprevention; Clinical Data; Collection; Colon; Colonoscopy; Colorectal; Colorectal Adenoma; Colorectal Cancer; Communicable Diseases; Communities; Data; Data Analyses; Data Analytics; Data Set; Development; Doctor of Philosophy; Economics; Ecosystem; Epidemiologist; Epidemiology; Event; Excision; Fluorescent in Situ Hybridization; Gastroenterologist; Genetic; Healthcare Systems; Hemorrhage; Human; Immunofluorescence Immunologic; Immunologist; Immunology; Incidence; Individual; Malignant Neoplasms; Maps; Methodology; Microbial Biofilms; Modeling; Neoplastic Cell Transformation; Operative Surgical Procedures; Participant; Pathologist; Patients; Perforation; Phenotype; Polyps; Prevention strategy; Reporting; Research; Research Personnel; Sampling; Seminal; Standardization; Sum; Surgeon; System; Tissues; United States; Universities; Work; adenoma; analytical tool; base; colorectal cancer prevention; cost effective; epidemiologic data; exome sequencing; high risk; human tissue; microbial; microbiome; molecular phenotype; mortality; novel; personalized diagnostics; premalignant; prevent; programs; prospective; proteogenomics; psychosocial; repository; risk stratification; single cell analysis; single-cell RNA sequencing; spatial relationship; tumor

PROJECT SUMMARY: Overall Colorectal cancer (CRC) is among the top three most prevalent cancers in global incidence and mortality. Most of these cancers develop from pre-cancerous adenomas. Colonoscopy is currently the most effective CRC prevention strategy. However, colonoscopy may fail to prevent carcinoma in as many as 24% of cases, is less effective at preventing proximal CRCs, is expensive for health care systems to implement, carries economic and psychosocial burdens for patients, and can be complicated by bleeding, perforation, and other adverse events. There is an unmet need to develop new preventive strategies and risk stratification models to address these and other issues. By analysis of whole human tissue, seminal work from Bert Vogelstein and co-workers demonstrated that CRC develops from an accumulation of genetic events as tumors evolve from small to large adenomas and, eventually, to cancers. More recently, our group reported the first comprehensive proteogenomic characterization of CRC, which also was from a bulk analysis of whole tissue Despite this wealth of data on CRC, we believe that the ability to provide the most effective precision diagnostics and preventive strategies can only be achieved with single-cell analysis. Through such a single-cell analysis, we propose to map spatial relationships across the spectrum of normal colon, early polyps, and late adenomas, including their unique stromal and microbial microenvironments. Aim 1: To construct a pre-cancer atlas of colorectal adenoma progression that depicts the spatial landscape of the tumor ecosystem, including the stroma and biofilm-associated microbiome, using single-cell (sc)RNA-seq, whole exome sequencing, multiplex immunofluorescence (MxIF), and species-specific bacterial fluorescence in situ hybridization (FISH). Aim 2: To integrate the activities and data from the Biospecimen, Tissue Characterization and Data Analysis Units for the prospective standardized collection and analysis of colorectal tissue, associated biospecimens, and related clinical and epidemiological data from 1,800 participants undergoing colonoscopy or surgical resection. Aim 3: To disseminate the pre-cancer atlas, related biospecimens, primary data sets and analytical tools to the Human Tumor Atlas Network (HTAN), the broader scientific community, and the lay public. To accomplish these aims, we have assembled a highly interactive and established team of investigators with complementary expertise (epidemiologists, gastroenterologists, pathologists, surgeons, systems biologists, bioinformaticians, cancer biologists, immunologists, and biofilms/infectious disease experts). To further optimize our novel methodologies for application to the prospectively collected samples from 1,800 atlas participants, we will leverage our existing large repository of colorectal adenomas and supporting biospecimens, generated and curated through an ongoing epidemiological project through 3 cycles of the Vanderbilt GI Special Programs of Research Excellence (SPORE). We are confident that our application, in toto, is greater than the sum of its parts, and we look forward to robust bi-directional interactions with HTAN.

项目摘要：结直肠癌是全球最常见的三种癌症之一。 全球发病率和死亡率。这些癌症中的大多数都是从癌前腺瘤发展而来的。结肠镜检查是 目前最有效的CRC预防策略。然而，结肠镜检查可能无法预防癌症 高达24%的病例在预防近端癌方面效果较差，对医疗保健系统来说代价高昂 实施，给患者带来经济和心理社会负担，并可能因出血而复杂化， 穿孔等不良事件。开发新的预防战略和风险的需求尚未得到满足 分层模型来解决这些和其他问题。通过对整个人体组织的分析，从 Bert Vogelstein和他的同事们证明了CRC是从如下遗传事件的积累发展而来的 肿瘤从小腺瘤演变为大腺瘤，最终演变为癌症。最近，我们的小组报告了 首次对结直肠癌进行了全面的蛋白质组学鉴定，这也是从整体上分析的 组织尽管有如此丰富的关于CRC的数据，我们相信能够提供最有效的精度 只有通过单细胞分析才能实现诊断和预防策略。通过这样一个单细胞 分析后，我们建议绘制正常结肠、早期息肉和晚期息肉的空间关系图 腺瘤，包括其独特的间质和微生物微环境。目标1：构建一个癌前状态 结直肠腺瘤进展图谱，描绘了肿瘤生态系统的空间景观，包括 基质和生物膜相关微生物组，使用单细胞(SC)RNA-SEQ，整个外显子组测序， 多重免疫荧光(MxIF)和物种特异性细菌荧光原位杂交(FISH)。 目的2：整合生物素、组织定征和数据分析的活动和数据 用于结直肠组织的前瞻性标准化收集和分析的单位、相关生物标本、 以及1800名接受结肠镜检查或外科手术的参与者的相关临床和流行病学数据 切除手术。目标3：传播癌前图谱、相关生物图谱、基本数据集和分析 向人类肿瘤图集网络(Htan)、更广泛的科学界和普通公众提供工具。至 为了实现这些目标，我们组建了一支高度互动和成熟的调查团队， 互补专业知识(流行病学家、胃肠病学家、病理学家、外科医生、系统生物学家、 生物信息学家、癌症生物学家、免疫学家和生物膜/传染病专家)。为了进一步 优化我们的新方法，以应用于从1,800份地图集中预期收集的样本 参与者，我们将利用我们现有的大型结直肠腺瘤存储库和支持 生物检疫，通过一个持续的流行病学项目产生和管理，通过3个周期 范德比尔特退伍军人研究卓越特别计划(孢子)。我们相信我们的应用程序，在 Toto，大于其各部分的总和，我们期待着与Htan进行强大的双向互动。