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: 10605225
• 负责人: Guido Erwin Michael Eibl
• 金额: $ 23.81万
• 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/10605225
• 关键词: Acceleration; 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; Genetic; Growth; Growth and Development function; Incidence; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Infiltrate; Intervention; KRAS oncogenesis; KRASG12D; Kinetics; Lesion; Life; Link; Lipids; Macrophage; Malignant Neoplasms; 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; Proliferating; 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; gastrointestinal; high risk; lipophilicity; 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.

项目总结