Microbiota pancreas interactions during cancer

癌症期间胰腺微生物群的相互作用

• 批准号: 10474561
• 负责人: Lewis C Murtaugh
• 金额: $ 18.68万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10474561
• 关键词: Ablation; Antibiotics; Area; Automobile Driving; Bacteria; Biological Markers; Caring; Colorectal; Complex; Cues; Death Rate; Detection; Development; Disease; Disease Marker; Disease Outcome; Early Diagnosis; Etiology; Event; Exhibits; Gastrointestinal tract structure; Genetic; Helicobacter pylori; Human; Immune; Immune Evasion; Immune response; Immunotherapy; Incidence; Individual; Intestines; KRAS oncogenesis; KRAS2 gene; Lesion; Lung; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Microbe; Minority; Modeling; Molecular; Mus; Obesity; Observational Study; Oncogenes; Pancreas; Pancreatic Diseases; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Patients; Phylogenetic Analysis; Play; Population; Porphyromonas gingivalis; Prevention; Publishing; Resistance; Risk; Risk Factors; Role; Smoking; Source; Symptoms; Testing; Therapeutic; Time; Transplantation; Tumor Immunity; United States; Work; antimicrobial peptide; base; biomarker development; cancer risk; chronic infection; commensal microbes; diagnostic tool; gut bacteria; gut microbes; gut microbiota; host microbiota; human microbiota; immunoregulation; improved; individual variation; knowledge base; member; microbial; microbial community; microbiota; mortality; mouse model; novel; novel strategies; pancreatic cancer patients; pancreatic ductal adenocarcinoma model; pancreatic neoplasm; pancreatic tumorigenesis; pathogenic bacteria; predictive marker; premalignant; restraint; targeted treatment; therapeutic target; translational study; tumor; tumor growth; tumor initiation; tumor progression; tumorigenesis

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer, with an incidence rate almost equal to its mortality rate. It has few strongly predictive risk factors, either genetic or environmental, it most often produces symptoms at advanced, inoperable stages, and it is resistant to both generic and targeted therapies. PDAC patients have had little benefit from the advances in early detection, prevention and treatment that have improved care for other common cancers. Intriguingly, however, recent evidence suggests that the microbial community of the gastrointestinal tract – the gut microbiota – represents a potential source of both biomarkers and therapeutic targets in PDAC. Published studies, and our own preliminary work, indicate that the microbiota is required for efficient pancreatic tumor initiation, although the underlying species and molecular mechanisms remain unknown. In addition, the microbiota of human PDAC patients is distinct from healthy controls, and early microbial alterations represent risk factors for later cancer development. Again, the mechanistic basis for this relationship is unknown, as it is a challenge to establish cause-and-effect relationships through observational studies, or through the use of conventional mouse models that lack control over the timing of tumor-initiating events. We hypothesize that the microbiota harbors a diverse array of cancer-promoting and -inhibiting species, acting at multiple times and through multiple mechanisms including modulation of immune responses, and that inter-individual heterogeneity in these species contributes to PDAC risk and disease outcome. To test this hypothesis, and to identify components of the microbiota as predictive markers of disease and targets for prevention and treatment, we propose to establish an experimental platform for functional analysis of the microbiota, based on a temporally-inducible mouse model of endogenous PDAC initiation and progression. We will use orthogonal analyses of time-specific and antibiotic-specific microbial ablation to dissect the roles of the endogenous mouse microbiota (Aim 1), and establish mice with “humanized” microbiota from individual PDAC patients and healthy controls to characterize the effects of disease-specific microbial communities on tumorigenesis and anti-tumor immunity (Aim 2). Our work will directly identify relevant members of the microbiota that contribute functionally to pancreatic cancer risk, and provide the knowledge base to develop microbial biomarkers and therapies to mitigate cancer progression.

抽象的 胰腺导管腺癌（PDAC）是最致命的癌症之一，其入射率 几乎等于其死亡率。它几乎没有强烈的预测危险因素，无论是遗传还是环境， 大多数经常在高级，无法操作的阶段产生符号，并且对通用和有针对性的符号具有抵抗力 疗法。 PDAC患者在早期检测，预防和治疗方面的进步几乎没有受益 改善了对其他常见癌症的护理。然而，有趣的是，最近的证据表明 胃肠道的微生物群落 - 肠道微生物群 - 代表了两者的潜在来源 PDAC中的生物标志物和治疗靶标。已发表的研究以及我们自己的初步工作，表明 有效的胰腺肿瘤倡议是必需的，尽管潜在的物种和 分子机制仍然未知。此外，人类PDAC患者的菌群与 健康对照和早期微生物改变代表了后来癌症发展的危险因素。再次， 这种关系的机械基础是未知的，因为建立因果关系是一个挑战 通过观察性研究或使用缺乏控制的传统鼠标模型的关系 在肿瘤发射事件的时机上。我们假设微生物群具有多种多样的 促进癌症和抑制物种，多次起作用，并通过多种机制 免疫反应的调节，这些物种中的个体异质性有助于PDAC 风险和疾病结果。检验这一假设，并识别微生物群的组成部分作为预测 疾病标志和预防和治疗的目标，我们建议建立一个实验平台 用于对微生物群的功能分析，基于内源性PDAC的暂时诱导小鼠模型 启动和进展。我们将使用特异性和抗生素特异性微生物的正交分析 消融以剖析内源性小鼠微生物群的作用（AIM 1），并用“人性化”建立了小鼠 来自个别PDAC患者和健康对照的微生物群，以表征疾病特异性的影响 肿瘤发生和抗肿瘤免疫的微生物群落（AIM 2）。我们的工作将直接确定 对胰腺癌风险作用的微生物群的相关成员，并提供 开发微生物生物标志物和疗法以减轻癌症进展的知识基础。