Regulation of Pancreatic Oncogenesis by the Gut Microbiome

总结 胰腺导管腺癌（PDA）是美国第五大癌症诊断，具有高致死性。 目前还没有有效的方法来预防或延迟PDA的发作，并且一旦发生，几乎没有有效的治疗选择 发生了转变。细菌生态失调正在成为癌症发生的帮凶， 胰腺恶性肿瘤，如结肠癌和肝癌。尽管如此，肠道微生物组还没有被清楚地 与远离肠腔或其引流的癌有关。然而，也有一些无关紧要的数据， 支持PDA和肠道细菌之间的联系。例如，患有口腔溃疡的患者的口腔微生物组 已发现PDA与对照受试者有很大不同。此外，我们的实验室已经获得了关键的 初步数据表明，肠道微生物组可能是PDA的重要调节因子， 在遗传易感宿主中的发展：（i）我们发现腔内肠道细菌可以直接进入 胰腺;（ii）PDA患者肠道中选择的细菌分类群的相对丰度较高， （iii）特异性模式识别受体（PRRs），其抑制炎症， 对微生物病原体的反应，在PDA肿瘤微环境（TME）中高度表达， 这些受体的激活加速肿瘤发生，而选择PRR缺陷的小鼠具有较慢的肿瘤发生。 PDA的进展;（iv）病原菌的腔内给药加速了 遗传易感的小鼠，而无菌小鼠被保护免于PDA。(v)选择细菌副产物 诱导调节性T细胞、M2极化巨噬细胞和髓源性抑制细胞的募集， PDA TME。基于这些数据，我们假设致病性肠道细菌驱动胰腺炎， 在高危宿主中通过激活特异性PRR（导致病原体诱导的免疫反应）发生肿瘤 镇压在目标1中，我们将定义发展PDA的小鼠的肠道和胰腺内微生物组 与WT小鼠相比，我们将对比与侵袭性PDA相关的微生物表型， 在基因型相同的宿主中缓慢进展的癌症，并确定PDA患者是否具有 与年龄匹配的对照患者相比，肠道和胰腺微生物组不同。在目标2中，我们将测试 肠道微生物通过检查是否直接调节微生物组来影响肿瘤发生的假设 改变了肿瘤的发展速度因此，我们将确定影响细胞增殖的特定腔内细菌。 胰腺癌发生的进展。在目标3中，我们将测试我们的假设，即选择管腔病原体 通过连接选择的Toll样受体诱导免疫抑制来促进胰腺肿瘤发生， NOD样受体。我们的实验将提供关键的新信息的机制， 胰腺癌发生我们还将确定新的风险因素，并为 开发旨在预防高危宿主PDA的创新疗法。

Summary Pancreatic ductal adenocarcinoma (PDA) is the 5th leading cancer diagnosis in the USA and is highly lethal. There are no effective means to prevent or delay PDA onset and few effective treatment options exist once transformation has occurred. Bacterial dysbiosis is emerging as an accomplice to carcinogenesis in extra- pancreatic malignancies such as colon and liver cancer. Nevertheless, the gut microbiome has not been clearly implicated in carcinomas remote from the intestinal lumen or its drainage. There are tangential data, however, that support an association between PDA and gut bacteria. For example, the oral microbiome in patients with PDA has been found to substantially differ from control subjects. Further, our laboratories have obtained critical preliminary data which suggest that the intestinal microbiome may be an important regulator of PDA development in genetically predisposed hosts: (i) We found that intraluminal gut bacteria can directly access the pancreas; (ii) The relative abundance of select bacterial taxa was higher in the gut of PDA patients compared with healthy individuals; (iii) Specific pattern recognition receptors (PRRs), which transduce inflammation in response to microbial pathogens, are highly expressed in the PDA tumor microenvironment (TME) and activation of these receptors accelerates tumorigenesis whereas mice deficient in select PRRs have slower progression of PDA; (iv) Endo-luminal administration of pathogenic bacteria accelerates tumorigenesis in genetically predisposed mice whereas germ-free mice are protected from PDA. (v) Select bacterial byproducts induce recruitment of regulatory T cells, M2-polarized macrophages, and myeloid derived suppressor cells to the PDA TME. Based on these data, we postulate that pathogenic gut bacteria drive pancreatic oncogenesis in at-risk hosts via activation of specific PRRs which leads to pathogen-induced immune suppression. In Aim 1 we will define the gut and intra-pancreatic microbiome in mice developing PDA compared with WT mice, we will contrast the microbial phenotypes associated with aggressive PDA compared with slowly progressive cancer in genotypically identical hosts, and determine whether humans with PDA harbor a distinct gut and pancreatic microbiome compared with age-matched control patients. In Aim 2, we will test our hypothesis that gut microbes influence oncogenesis by examining whether directly modulating the microbiome alters the rate of tumor progression. As such, we will identify the specific endoluminal bacteria which affect the progression of pancreatic oncogenesis. In Aim 3, we will test our hypothesis that select luminal pathogens promote pancreatic tumorigenesis by inducing immune suppression via ligation of select Toll-like receptors and NOD-like receptors. Our experiments will provide critical new information on the mechanism of pancreatic oncogenesis. We will also identify novel risk factors and provide guidance for the development of innovative therapeutics aimed at PDA prevention in at-risk hosts.