Microbiota pancreas interactions during cancer

摘要 摘要胰腺导管腺癌是一种致命性最强的癌症，其发病率较高。 几乎等于它的死亡率。它几乎没有很强的预测性风险因素，无论是遗传还是环境因素，它 最常见的是在晚期、无法手术时出现症状，并且对通用和靶向都有耐药性。 治疗。PDAC患者几乎没有从早期发现、预防和治疗方面的进步中受益 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--肠道微生物区系--是两者的潜在来源 PDAC中的生物标志物和治疗靶点。已发表的研究和我们自己的初步工作表明， 微生物区系是有效启动胰腺肿瘤所必需的，尽管潜在的物种和 分子机制尚不清楚。此外，人类PDAC患者的微生物区系与 健康对照和早期微生物改变是后期癌症发展的风险因素。再说一次， 这种关系的机制基础尚不清楚，因为要确定因果关系是一项挑战 通过观察性研究或通过使用缺乏控制的传统老鼠模型 启动肿瘤事件的时间。我们假设微生物区系中有不同种类的 促进和抑制癌症的物种，通过多种机制多次发挥作用，包括 免疫反应的调节，以及这些物种个体间的异质性有助于PDAC 风险和疾病后果。为了验证这一假设，并确定微生物区系的成分是可预测的 疾病标志物和防治目标，我们建议建立一个实验平台 用于微生物区系的功能分析，基于内源性PDAC的时间诱导的小鼠模型 开始和进展。我们将使用时间特定的和抗生素特定的微生物的正交分析 消融以解剖内源性小鼠微生物区系的作用(目标1)，并建立“人源化”小鼠 来自个体PDAC患者和健康对照的微生物区系以表征疾病特异性的影响 关于肿瘤发生和抗肿瘤免疫的微生物群落(目标2)。我们的工作将直接确定 微生物区系中在功能上对胰腺癌风险有贡献的相关成员，并提供 开发微生物生物标志物和治疗方法以减缓癌症进展的知识库。

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.