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

项目1：肥胖促进的胰腺癌中的脂肪组织炎症

• 批准号: 10398845
• 负责人: Guido Erwin Michael Eibl
• 金额: $ 23.84万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10398845
• 关键词: Adipocytes; Adipose tissue; Animal Model; Anti-Inflammatory Agents; Attenuated; CCL2 gene; Cells; Chemoprevention; Chronic Disease; Complex; Development; Diabetes Mellitus; Diet; Dietary Component; Disease; Dose; Economics; Excision; FDA approved; Growth; Growth and Development function; Incidence; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Infiltrate; Intervention; KRAS oncogenesis; KRASG12D; Kinetics; Lesion; Life; Link; Lipids; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of pancreas; Mediating; Metabolic Diseases; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Non-Malignant; Obesity; Obesity associated cancer; Organoids; Outcome; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Positive Reinforcements; Primary Prevention; Production; Risk Factors; Role; Secondary Prevention; Signal Transduction; Societies; Sociology; TLR4 gene; Testing; Time; Tissues; Transcription Coactivator; Tumor Promotion; Visceral; cancer prevention; cytokine; design; diet-induced obesity; drug repurposing; efficacious intervention; high risk; lipophilicity; macrophage; mouse model; novel; novel strategies; obese patients; obesity genetics; obesogenic; pancreas development; pancreatic cancer model; pancreatic ductal adenocarcinoma cell; prevent; programs; rho; translational approach; translational impact; tumor

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.

项目概要 有大量证据表明肥胖是多种慢性病发生的危险因素， 包括胰腺导管腺癌（PDAC）。这些疾病带来了令人难以置信的经济和 给社会带来的社会负担。尽管潜在的机制可能是多方面的，但炎症 毫无疑问，肥胖与癌症之间的联系起着重要作用。炎症细胞浸润如 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 发展和成长。许多动物模型已证明抗炎策略可以延迟或 预防癌症的发展，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，以及（胃肠道） 癌症。在之前的研究中发现，致胖饮食可以显着加速发育和 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。这是关联的 胰腺和内脏脂肪组织（VAT）严重炎症。总体假设 该项目的主要内容是肥胖会导致 VAT 炎症，这是 PDAC 的关键（促进）驱动因素 发展和成长。使用 FDA 批准的新用途药物治疗肥胖相关的 VAT 炎症 可能代表了一种有趣且新颖的策略来阻止 PDAC 的发展和进展。特定目标 1 将研究肥胖引起的 AT 炎症和 PDAC 发展的动力学。的影响 将饮食引起的肥胖与遗传引起的肥胖进行比较。确定有效的介入治疗和 转化策略他汀类药物对 AT 炎症和 PDAC 的剂量和时间依赖性影响 发展将在具体目标 2 中进行评估。他汀类药物作用的分子机制 AT 炎症的影响以及 AT 炎症对 PanIN/类器官离体生长的影响将在 具体目标 3，重点关注 YAP/TAZ，即 Hippo 通路中的转录共激活因子。这些研究将 提供证据证明肥胖引起的 VAT 炎症在 PDAC 生长中发挥关键作用，并将鉴定新的 机制途径和目标。由于他汀类药物被广泛使用并且 FDA 批准了药物，因此成功 研究的完成将对 PDAC 患者产生直接的转化影响。一般来说， 结果也可能适用于其他与肥胖相关的癌症，甚至非恶性慢性疾病。