Project 1: Adipose tissue inflammation in obesity-promoted pancreatic cancer

项目总结 有大量证据表明，肥胖是几种慢性病发展的风险因素， 包括胰腺导管腺癌(PDAC)。这些疾病造成了令人难以置信的经济和 社会的社会学负担。尽管潜在的机制可能是多方面的，但炎症 当然，在肥胖和癌症之间的联系中起着重要作用。侵袭性炎性细胞作为 全身和局部水平的促炎介质为肿瘤提供了理想的微环境 发展壮大。抗炎策略已经在许多动物模型中被证明可以延缓或 防止癌症的发展，被广泛认为是有趣的癌症预防方法。在……里面 此外，肥胖相关的脂肪组织炎症，特别是内脏脂肪组织炎症， 与代谢性疾病的发展密切相关，例如2型糖尿病和(胃肠道) 癌症。在以前的研究中，肥胖饮食被发现显着地加速了发育和 PDAC前体病变(胰腺上皮内瘤变：Panin)的进展，并增加 条件KrasG12D(KC)小鼠模型中侵袭性和转移性PDAC的发生率。这是一种关联 胰腺和内脏脂肪组织(VAT)严重发炎。最重要的假设 该项目的重点是肥胖导致增值税炎症，这是PDAC的关键(促进)驱动因素 发展壮大。FDA批准的、用途改变的药物针对肥胖相关的增值税炎症 可能代表了一种耐人寻味的新策略来防止PDAC的发展和进展。以特定的目标 1研究肥胖诱导的AT炎症和PDAC形成的动力学。的影响 饮食导致的肥胖将与遗传导致的肥胖进行比较。确定有效的干预和治疗方法 翻译策略：他汀类药物对AT炎症和PDAC的剂量和时间依赖效应 开发将在特定目标下进行评估2.他汀类药物作用的分子机制 关于AT炎症以及AT炎症对Panin/有机物体外生长的影响将在#年确定 具体目标3，重点是YAP/TAZ，河马途径中的转录共激活因子。这些研究将 提供肥胖导致的增值税炎症在PDAC生长中的关键作用的证据，并将确定新的 机械化的路径和目标。由于他汀类药物被广泛使用，FDA批准的药物成功 这些研究的完成将对PDAC患者产生立竿见影的影响。一般而言， 研究结果也可能适用于其他与肥胖相关的癌症，甚至是非恶性慢性病。

PROJECT SUMMARY There is substantial evidence that obesity is a risk factor for the development of several chronic diseases, including pancreatic ductal adenocarcinoma (PDAC). These diseases pose an incredible economic and sociologic burden to society. Although the underlying mechanisms are likely multi-faceted, inflammation certainly plays an important role in the link between obesity and cancer. Infiltrating inflammatory cells as well as systemic and local levels of pro-inflammatory mediators provide in ideal micro-milieu for tumor development and growth. Anti-inflammatory strategies have been shown in many animal models to delay or prevent the development of cancers and are widely considered intriguing approaches for cancer prevention. In addition, obesity-associated adipose tissue inflammation, in particular visceral adipose tissue inflammation, correlates strongly to the development of metabolic diseases, e.g. type 2 diabetes mellitus, and (gastrointestinal) cancer. In previous studies an obesogenic diet was found to significantly accelerate the development and progression of PDAC precursor lesions (pancreatic intraepithelial neoplasia: PanIN), and to increase the incidence of invasive and metastatic PDAC in the conditional KrasG12D (KC) mouse model. This was associated with a substantial inflammation of the pancreas and visceral adipose tissue (VAT). The overarching hypothesis of this Project is that obesity leads to VAT inflammation, which is a critical (promotional) driver of PDAC development and growth. Targeting obesity-associated VAT inflammation with FDA-approved, repurposed drugs may represent an intriguing and novel strategy to prevent PDAC development and progression. In Specific Aim 1 the kinetics of obesity-induced AT inflammation and PDAC development will be investigated. The effects of diet-induced obesity will be compared with genetically-induced obesity. To identify efficacious interventional and translational strategies the dose- and time-dependent effects of statins on AT inflammation and PDAC development will be evaluated in Specific Aim 2. The molecular mechanisms underlying the effects of statins on AT inflammation and the effects of AT inflammation on PanIN/organoid growth ex vivo will be determined in Specific Aim 3 with a focus on YAP/TAZ, transcriptional co-activators in the Hippo pathway. The studies will provide evidence of a critical role of obesity-induced VAT inflammation in PDAC growth and will identify novel mechanistic pathways and targets. Since statins are widely used and FDA-approved drugs the successful completion of the studies will have an immediate and translational impact on patients with PDAC. Generally, the results may also be transferable to other obesity-related cancers and even non-malignant chronic diseases.