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

项目总结 肥胖会增加患胰腺癌(PDAC)的风险，但其发病机制 这些效应和肿瘤间质所起的确切作用还不是很清楚。用有胰腺的小鼠- 致癌突变Kras(KC小鼠)的特异性表达，肥胖饮食被发现显著增加 激活的间质肌成纤维细胞(又名胰星状细胞，PASC)的数量及其沉积 细胞外基质(ECM)蛋白质，尤其是那些促进基质硬化的蛋白质。肥胖引起的心脏功能改变 胰腺纤维化间质与巨噬细胞数量增加和各种不同水平的 细胞因子、趋化因子和生长因子具有免疫调节能力，加速肿瘤进展 肿瘤和侵袭性PDAC的发生率增加。尽管数据强烈地表明了促肿瘤作用 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(S)及其 表型特征似乎比最初认为的要复杂得多。研究提供的证据表明 细胞外信号胰岛素、胰岛素样生长因子-1(IGF-1)、瘦素、脂多糖和选定的白介素类； 细胞内信号包括mTOR/Akt、STAT3和YES相关蛋白1(YAP)在调控中起关键作用 PASC的表型和促进PASC的促癌作用。这些影响很可能是由PASC介导的 促进肿瘤细胞生长和诱导细胞凋亡抵抗的纤维炎症信号。此外，PASC是 发现调节肿瘤巨噬细胞分化为有利于肿瘤免疫抑制的表型 进步。令人感兴趣的是最近对大型数据库的回顾分析结果，这些患者患有 服用辛伐他汀的PDAC患者预后显著改善，无病生存期延长。还有，Pilot 研究表明，二甲双胍可通过调节细胞代谢、自噬和 纤维炎症介质的表达。在这项提议中，假设肥胖会产生独特的 在发育中的PDAC的微环境中负责表型变化的信号 PASC因此它们产生促进癌细胞增殖和抗凋亡的因子 细胞以及将免疫反应转变为有利于肿瘤的状态。另据预计，辛伐他汀 二甲双胍可减弱这种促进PASC的作用，并可能有助于预防肥胖诱导 PDAC开发。这一假设将通过(1)确定选择性淘汰的后果来检验 PASC在KC小鼠肥胖诱导的PDAC促进中的作用；(2)建立PASC的途径和细胞过程 在间质PASC中负责肥胖促进的致癌表型；(3)阐明串扰 (4)测定辛伐他汀对PASC、癌细胞和肿瘤巨噬细胞的影响。 二甲双胍联合应用对肥胖小鼠PASC促肿瘤表型的影响。总而言之，这是 该提案旨在展示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。

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.