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

项目摘要 有大量证据表明，肥胖是几种慢性疾病发展的危险因素， 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 社会负担。虽然潜在的机制可能是多方面的，炎症 在肥胖和癌症之间的联系中扮演着重要的角色。浸润的炎症细胞 以及全身和局部水平的促炎介质为肿瘤提供了理想的微环境 发展和增长。抗炎策略已在许多动物模型中显示出延迟或减轻炎症。 预防癌症的发展，并且被广泛认为是预防癌症的有趣方法。在 此外，肥胖相关的脂肪组织炎症，特别是内脏脂肪组织炎症， 与代谢疾病的发展密切相关，例如2型糖尿病和（胃肠道） 癌在以前的研究中，发现致胖饮食会显著加速发育， PDAC前体病变（胰腺上皮内瘤变：PanIN）的进展，并增加 条件性KrasG 12 D（KC）小鼠模型中侵袭性和转移性PDAC的发生率。这与 胰腺和内脏脂肪组织（VAT）有严重炎症。总体假设 肥胖导致VAT炎症，这是PDAC的关键（促进）驱动因素 发展和增长。用FDA批准的再利用药物靶向肥胖相关的VAT炎症 可能代表了一种有趣的和新颖的策略，以防止PDAC的发展和进展。具体目标 1将研究肥胖诱导的AT炎症和PDAC发展的动力学。的影响 将饮食诱导的肥胖症与遗传诱导的肥胖症进行比较。确定有效的干预措施， 他汀类药物对AT炎症和PDAC的剂量和时间依赖性作用 将在具体目标2中进行评估。他汀类药物作用的分子机制 以及AT炎症对离体PanIN/类器官生长的影响将在 具体目标3，重点是雅普/TAZ，Hippo途径中的转录共激活因子。这些研究将 提供了肥胖诱导的VAT炎症在PDAC生长中的关键作用的证据，并将确定新的 机械路径和目标。由于他汀类药物的广泛使用和FDA批准的药物， 研究的完成将对PDAC患者产生直接和转化的影响。一般 研究结果也可用于其他与肥胖有关的癌症，甚至非恶性慢性疾病。

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.