Project 3: Role of the pancreatic fibroinflammatory microenvironment in obesity-promoted pancreatic cancer

项目3：胰腺纤维炎症微环境在肥胖促进的胰腺癌中的作用

• 批准号: 10605240
• 负责人: STEPHEN J PANDOL
• 金额: $ 24.66万
• 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/10605240
• 关键词: Acceleration; Animals; Apoptosis; Attenuated; Autophagocytosis; Calories; Cancer Cell Growth; Cancer Death Rates; Cancer Etiology; Cell Count; Cell physiology; Cells; Characteristics; Chemoprevention; Chemopreventive Agent; Cholesterol; Chronic; Coculture Techniques; Collaborations; Complex; Cues; Data; Databases; Death Rate; Deposition; Development; Diabetes Mellitus; Diagnosis; Diet; Disease; Disease-Free Survival; Early Diagnosis; Environment; Excision; Experimental Models; Extracellular Matrix Proteins; FRAP1 gene; Fatty acid glycerol esters; Genetic; Growth Factor; Immune; Immune response; Immune system; Incidence; Induction of Apoptosis; Inflammatory; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Interleukin-13; Interleukin-4; Interleukins; KRAS oncogenesis; KRASG12D; Leptin; Macrophage; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mediator; Metabolism; Metformin; Mind; Mitochondria; Monitor; Mus; Mutation; Myofibroblast; Obese Mice; Obesity; Oncogenic; Operative Surgical Procedures; Organoids; Outcome; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Pilot Projects; Play; Prevention strategy; Process; Proliferating; Proteins; Regimen; Relapse; Research Personnel; Resectable; Resistance; Risk; Role; ST13 gene; STAT3 gene; Signal Transduction; Simvastatin; Survival Rate; System; Testing; Time; Tissues; Transforming Growth Factor beta; Tumor Promotion; Weight Gain; Wild Type Mouse; cancer cell; cancer risk; cell growth; cell type; chemokine; cytokine; design; diet-induced obesity; extracellular; fighting; high risk population; immunoregulation; improved; improved outcome; in vitro Model; in vivo; insight; insulin signaling; interest; mortality; mouse model; mutant; neoplastic cell; novel; obesity prevention; obesogenic; pancreatic cancer model; pancreatic stellate cell; pre-clinical; prevent; prevention clinical trial; programs; response; success; tumor; tumor microenvironment; tumor progression; tumorigenesis; tumorigenic

PROJECT SUMMARY Obesity increases the risk of developing pancreatic adenocarcinoma (PDAC), but the mechanisms underlying these effects and the precise role played by the tumor stroma are not well understood. Using mice with pancreas- specific expression of oncogenic mutant Kras (KC mice), obesogenic diets were found to markedly increase the number of activated stromal myofibroblasts (aka pancreatic stellate cells, PaSC) and their deposition of extracellular matrix (ECM) proteins, especially those promoting matrix stiffening. Obesity-induced changes in the pancreatic fibrotic stroma are associated with increased numbers of macrophages and levels of various cytokines, chemokines and growth factors with immunomodulation capacity, acceleration of the progression of the tumor and increased incidence of invasive PDAC. Although the data strongly suggest a pro-tumor role for stromal PaSC in obesity-induced PDAC promotion, the precise role(s) of these cells in PDAC and their phenotypic characteristics appear more complex than initially perceived. Studies provided evidence that the extracellular signals insulin, insulin-like growth factor 1 (IGF-1), leptin, LPS and selected interleukins; and intracellular signals including mTOR/Akt, STAT3, and yes-associated protein 1 (YAP) play key roles in regulating PaSC phenotypes and in promoting the pro-cancer effects of PaSC. These effects are likely mediated by PaSC fibroinflammatory signals that boost tumor cell growth and induce apoptosis resistance. Moreover, PaSC were found to regulate tumor macrophage differentiation into immunosuppressive phenotypes conducive of tumor progression. Of interest are recent findings from retrospective analysis of large databases that patients with PDAC have significantly improved outcome and longer disease-free survival if they take simvastatin. Also, pilot studies indicate that metformin can modulate PaSC responses by regulating cellular metabolism, autophagy and expression of fibro-inflammatory mediators. In this proposal, the hypothesis is that obesity produces unique signals in the microenvironment of developing PDAC that are responsible for phenotypic alterations in the PaSC so that they produce factors that promote proliferation and apoptosis resistance in the cancer cells as well as shift the immune response to a pro-tumor state. It is also anticipated that simvastatin and metformin attenuate this PaSC promotion and may be useful for prevention of obesity-induced PDAC development. This hypothesis will be tested by (1) determining the consequences of selective elimination of PaSC in KC mice on obesity-induced PDAC promotion; (2) establishing the pathways and cellular processes in the stromal PaSC responsible for the pro-cancer phenotype promoted by obesity; (3) elucidating crosstalk between PaSC, cancer cells and tumor macrophages; and (4) determining the effects of simvastatin in combination with metformin on the pro-tumor phenotype of PaSC observed in the obese mice. In sum, this proposal is designed to show the roles and mechanisms of PaSC-induced tumor promotion occurring in obesity, and to provide pre-clinical evidence for chemopreventive strategies for pancreatic cancer.

项目摘要 肥胖会增加患胰腺癌（PDAC）的风险，但其潜在机制 这些效应以及肿瘤间质所发挥的精确作用还不清楚。使用有胰腺的老鼠- 致癌突变Kras的特异性表达（KC小鼠），发现致肥胖饮食显著增加 激活的基质肌成纤维细胞（又称胰腺星状细胞，PaSC）的数量及其沉积 细胞外基质（ECM）蛋白，尤其是促进基质硬化的那些。肥胖引起的 胰腺纤维化间质与巨噬细胞数量增加和各种 具有免疫调节能力的细胞因子、趋化因子和生长因子， 肿瘤和侵袭性PDAC的发病率增加。尽管数据强烈表明， 基质PaSC在肥胖诱导的PDAC促进中的作用，这些细胞在PDAC中的确切作用及其 表型特征似乎比最初认为的更复杂。研究表明， 细胞外信号胰岛素、胰岛素样生长因子1（IGF-1）、瘦素、LPS和选择的白细胞介素;和 细胞内信号包括mTOR/Akt、STAT 3和yes相关蛋白1（雅普）在调节细胞凋亡中起关键作用。 PaSC表型和促进PaSC的促癌作用。这些作用可能由PaSC介导 纤维炎症信号促进肿瘤细胞生长并诱导凋亡抗性。此外，PaSC 发现调节肿瘤巨噬细胞分化为有利于肿瘤的免疫抑制表型 进展感兴趣的是最近对大型数据库进行回顾性分析的结果， PDAC患者服用辛伐他汀可显著改善预后，延长无病生存期。另外，飞行员 研究表明，二甲双胍可通过调节细胞代谢、自噬和 纤维炎性介质的表达。在这个提案中，假设是肥胖会产生独特的 PDAC微环境中负责表型改变的信号， 使其产生促进癌细胞增殖和抗凋亡的因子 细胞，并将免疫反应转移到促肿瘤状态。还预期辛伐他汀 和二甲双胍减弱了这种PaSC促进作用， PDAC开发。这一假设将通过（1）确定选择性消除的后果 KC小鼠PaSC对肥胖诱导的PDAC的促进作用;（2）建立通路和细胞过程 在负责肥胖促进的促癌表型的基质PaSC中;（3）阐明串扰 在PaSC、癌细胞和肿瘤巨噬细胞之间;和（4）确定辛伐他汀在PaSC、癌细胞和肿瘤巨噬细胞中的作用。 在肥胖小鼠中观察到的PaSC的促肿瘤表型上，总之，这 该提案旨在显示PaSC诱导的肿瘤促进发生的作用和机制 并为胰腺癌的化学预防策略提供临床前证据。