CMA: Cancer Stem Cells in the Pathogenesis and Treatment of Colorectal Cancer

CMA：癌症干细胞在结直肠癌的发病机制和治疗中的作用

• 批准号: 10454794
• 负责人: JOSEPH R PISEGNA
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10454794
• 关键词: Ablation; Address; Affect; Aftercare; Animal Model; Biological Markers; Cancer Etiology; Cancer Model; Cessation of life; Chicago; Clinic; Clinical; Colon Adenocarcinoma; Colon Carcinoma; Colorectal Adenocarcinoma; Colorectal Adenoma; Colorectal Cancer; Colorectal Neoplasms; Colorectal Polyp; Development; Diagnosis; Disease; Disease remission; Drug Targeting; Epidemiology; Event; Excision; Exposure to; Feces; Female; Funding; Fusobacterium; Future; Gene Expression Profile; Genes; Genetic Transcription; Genomics; Germ-Free; Healthcare; Histologic; Human; Immune; Immune response; Immunotherapy; Incidence; Interdisciplinary Study; Investigation; Lead; Link; Malignant Neoplasms; Mediating; Metabolism; Microbe; Micrometastasis; Molecular; Molecular Profiling; Mouse Strains; Mus; Muscarinic M3 Receptor; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Pathogenesis; Pathology; Pathway interactions; Patients; Phenotype; Population; Prevention; Prognosis; Provider; Radiation; Recurrence; Regulation; Reproducibility; Research; Resources; Rest; Risk; Risk Assessment; Role; Sampling; Study models; Technology; Toxin; Transcript; Treatment Effectiveness; Treatment outcome; Tumor Cell Invasion; Tumor Immunity; Tumor Tissue; Tumor-infiltrating immune cells; Untranslated RNA; Validation; Veterans; base; cancer cell; cancer stem cell; chemotherapy; clinical center; clinical infrastructure; clinical practice; cohort; colorectal cancer progression; colorectal cancer risk; colorectal cancer treatment; comorbidity; diet and cancer; experimental study; follow-up; genotoxicity; gut microbiome; gut microbiota; host microbiome; human microbiota; improved; intestinal adenoma; male; meetings; member; metabolome; metabolomics; microbial; microbial composition; microbiome; microbiome analysis; microbiota; mimetics; mouse model; novel; novel strategies; polysulfated glycosaminoglycan; probiotic therapy; prognostication; response; screening; transcriptome; transcriptomics; treatment response; tumor; tumorigenesis

ABSTRACT This proposal is being submitted as part of a group of linked merit review applications from nationwide VA experts in colorectal cancer (CRC) who have formed a colorectal cancer cell-genomics consortium (VA4C) after participating in a successful field-based meeting in Chicago in May 2017 (funded by VA ORD). Specifically, this proposal will be part of a cluster of merit review projects that are aimed at advancing our understanding of CRC pathogenesis and treatment response with a focus on the roles of the microbiome and CRC stem cells. The importance of the intestinal microbiome to the development and progression of CRC is supported by a range of evidence including epidemiological links between diet and CRC risk, reproducible associations of specific microbes such as Fusobacterium with human CRC, mouse models indicating augmentation of CRC formation and metastasis by microbiota, and mouse models showing that the microbiome modulates chemotherapy response. We hypothesize that: 1) The intestinal microbiome, through direct invasion of tumor tissue and release of bioactive microbial products, is associated with specific CRC clinical/histologic phenotypes and molecular subclasses defined by transcriptional profiles. 2) The intestinal microbiome influences the risk of recurrence after surgery and chemotherapy by modulating anti-tumor immunity and the metabolism of chemotherapeutics. 3) The treatment of locally advanced CRC with surgical resection and chemotherapy alters the intestinal microbiome, which may influence the likelihood of future recurrences. To study these hypotheses, in Aim 1 we will utilize the multi-center clinical infrastructure of this CMA to collect fecal and tumor samples from 400 male and female Veterans with stage I-III CRC for analysis of the microbiome, metabolome, and transcriptome. Intestinal microbes and metabolites will be identified that are associated with tumor phenotype and molecular signature, as defined by gene transcripts, functional pathways and non-coding RNAs. In Aim 2, we will perform longitudinal follow-up of 200 Veterans with stage II- III colorectal cancer to elucidate baseline microbes and metabolites that predict subsequent risk for recurrence. In addition, we will obtain fecal samples before, during and after surgery then chemotherapy, and annually thereafter to identify microbial shifts with treatment and their association with future recurrence. In Aim 3, we will link compositional and functional shifts in the intestinal microbiome to CRC by using the C57BL/6 ApcMin strain of mice that is highly susceptible to spontaneous intestinal adenoma formation. We will examine the effect of colonization with human microbiota obtained from patients with high or low immune infiltration and immune transcriptional state, to assess adenoma/CRC formation and the intratumor immune response. We will also study the response to chemotherapy in mice engrafted with CRC cells and colonized with the stool of patients that had a recurrence, or a sustained remission, to evaluate microbiome-mediated differences in therapeutic response.

抽象的 该提案正在作为来自全国弗吉尼亚州的一系列链接绩效审查申请的一部分提交 结交结直肠癌细胞基因组学联盟（VA4C）的结直肠癌专家（CRC） 在2017年5月在芝加哥参加了成功的现场会议之后（由VA Ord资助）。 具体而言，该提案将成为一系列优异审查项目的一部分，旨在推动我们的 了解CRC的发病机理和治疗反应，重点是微生物组和 CRC干细胞。肠道微生物组对CRC的发展和发展的重要性是 由一系列证据支持，包括饮食与CRC风险之间的流行病学联系，可再现 特定微生物（例如梭菌与人CRC）的关联，指示小鼠模型 通过微生物群增强CRC的形成和转移，小鼠模型表明 微生物组调节化疗反应。我们假设：1）通过 肿瘤组织的直接侵袭和生物活性微生物产物的释放与特定的CRC有关 由转录曲线定义的临床/组织学表型和分子亚类。 2）肠道 微生物组通过调节抗肿瘤来影响手术和化学疗法后复发的风险 免疫力和化学治疗的代谢。 3）手术治疗局部晚期CRC 切除和化学疗法改变肠道微生物组，这可能会影响未来的可能性 复发。为了研究这些假设，在AIM 1中，我们将利用这一点的多中心临床基础设施 CMA从400名男性和女性退伍军人中收集粪便和肿瘤样品，以分析I-III期CRC 微生物组，代谢组和转录组。将确定肠道微生物和代谢物 与肿瘤表型和分子特征相关，如基因转录本的定义 途径和非编码RNA。在AIM 2中，我们将对具有II期的200名退伍军人进行纵向随访。 III结直肠癌以阐明基线微生物和代谢产物，以预测随后的复发风险。 此外，我们将在手术之前，期间和之后获得粪便样本，然后再进行化学疗法，并每年获得 此后，通过治疗及其与未来复发的关联来确定微生物的转移。在AIM 3中，我们 通过使用C57BL/6 APCMIN 高度易于自发肠道腺瘤的小鼠的菌株。我们将检查 从高或低免疫浸润的患者中获得的人类微生物群定植的影响 免疫转录状态，以评估腺瘤/CRC形成和肿瘤内免疫反应。我们将 还研究了用CRC细胞植入的小鼠的化学疗法的反应，并用 患有复发或持续缓解的患者，以评估微生物组介导的差异 治疗反应。