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 该提案是作为全国退伍军人事务部一系列链接的绩效审查申请的一部分提交的 结直肠癌 (CRC) 专家组成了结直肠癌细胞基因组学联盟 (VA4C) 2017 年 5 月在芝加哥成功参加了一次现场会议（由 VA ORD 资助）。 具体来说，该提案将成为一系列绩效审查项目的一部分，这些项目旨在推进我们的 了解 CRC 发病机制和治疗反应，重点关注微生物组的作用和 结直肠癌干细胞。肠道微生物群对 CRC 发生和进展的重要性是 得到一系列证据的支持，包括饮食与结直肠癌风险之间的流行病学联系，可重复 特定微生物（例如梭杆菌）与人类结直肠癌的关联，小鼠模型表明 微生物群增强了结直肠癌的形成和转移，小鼠模型表明 微生物组调节化疗反应。我们假设：1）肠道微生物组，通过 直接侵入肿瘤组织并释放生物活性微生物产物，与特定的结直肠癌相关 由转录谱定义的临床/组织学表型和分子亚类。 2）肠道 微生物组通过调节抗肿瘤作用影响手术和化疗后复发的风险 免疫和化疗药物的代谢。 3）局部晚期结直肠癌的手术治疗 切除和化疗会改变肠道微生物群，这可能会影响未来的可能性 复发。为了研究这些假设，在目标 1 中，我们将利用该中心的多中心临床基础设施 CMA 将从 400 名患有 I-III 期 CRC 的男性和女性退伍军人身上收集粪便和肿瘤样本进行分析 微生物组、代谢组和转录组。肠道微生物和代谢物将被鉴定为 与肿瘤表型和分子特征相关，如基因转录本、功能 途径和非编码RNA。在目标 2 中，我们将对 200 名处于 II 阶段的退伍军人进行纵向随访 III 结直肠癌阐明预测后续复发风险的基线微生物和代谢物。 此外，我们将在手术前、手术中和手术后以及化疗后每年采集粪便样本 然后确定治疗过程中微生物的变化及其与未来复发的关系。在目标 3 中，我们 将使用 C57BL/6 ApcMin 将肠道微生物组的组成和功能变化与 CRC 联系起来 对自发性肠腺瘤形成高度敏感的小鼠品系。我们将检查 从免疫浸润高或低的患者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 形成和瘤内免疫反应。我们将 还研究了移植了 CRC 细胞并用粪便定植的小鼠对化疗的反应 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。