Counteracting molecular mechanisms of obesity dependent PDAC progression

抵消肥胖依赖性 PDAC 进展的分子机制

基本信息

批准号：
10300996
负责人：
Michael Nathan VanSaun
金额：
$ 34.13万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-10 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10300996
关键词：
Adipocytes Adipose tissue Adverse effects Agonist Biological Assay CXCL5 gene Cells Chemotactic Factors Chemotaxis Development EGF gene Epithelial Financial compensation Genetic Models Genetically Engineered Mouse Goals Growth Immune In Vitro Incidence Inflammation Inflammatory Inflammatory Response Injections Interleukin-1 Interleukin-6 Interleukin-8 KRAS2 gene KRASG12D Knowledge Lead Leptin Lesion Ligands Malignant Neoplasms Malignant neoplasm of pancreas Mediating Mediator of activation protein Molecular Mus Myeloid-derived suppressor cells Neoplasm Metastasis Neutrophil Infiltration Obese Mice Obesity Obesity Epidemic Outcome PTPN11 gene Pancreas Pancreatic Ductal Adenocarcinoma Pathway interactions Pharmacology Phenotype Population Production Protein Tyrosine Phosphatase Ras/Raf Resistance Risk Factors Role STAT3 gene Serum Signal Transduction Supplementation Therapeutic Therapeutic Uses Up-Regulation Xenograft Model Yin-Yang adipokines adiponectin cancer risk cytokine design in vivo inhibitor insight leptin receptor macrophage migration neoplastic cell neutrophil novel novel therapeutic intervention novel therapeutics obese person overexpression pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model prevent receptor recruit treatment strategy tumor tumor growth tumor microenvironment tumor progression tumorigenic

项目摘要

The epidemic of obesity is a significant risk factor in five of the six most common forms of cancer, including pancreatic ductal adenocarcinoma (PDAC). Inflammatory responses associated with obesity lead to the dysregulation of adipose secreted cytokines, referred to as adipokines. In obese individuals, serum levels of leptin, a pro-tumorigenic adipokine, dramatically increase while the anti-tumorigenic adiponectin levels decrease, ultimately promoting cancer progression. Our efforts have shown that obesity induces adipocytes to increase leptin and IL-6 secretion, which exert pro-tumorigenic effects in PDAC cells that drive proliferation, migration and in vivo tumor growth. We have now identified that the anti-tumorigenic adipokine, adiponectin, counteracts the effects of pro-tumorigenic adipokines in obesity associated PDAC progression through multiple mechanisms. First, adiponectin antagonizes leptin and IL-6 induced activation of STAT3 and ERK signaling in PDAC cells resulting in suppression of PDAC growth. Second, adiponectin blocks activation of the Src homology region 2 containing protein tyrosine phosphatase (SHP-2), a key mediator of leptin and IL-6-induced RAF-RAS-ERK signaling. Third, adiponectin effectively inhibits the secretion of inflammatory cell attractants from tumor cells. Our results validate that adiponectin is a critical negative regulator of obesity associated PDAC progression and provide a novel therapeutic strategy for the treatment of PDAC. The goal of this proposal is to determine whether counteracting adipose secreted cytokines can inhibit PDAC progression. Our central hypothesis is that adiponectin overcomes innate resistance of PDAC by antagonizing adipokine mediated RAS activity through suppression of SHP-2 and by blocking inflammatory cell recruitment into the tumor microenvironment. The overall objective is to determine whether adiponectin represents a viable therapeutic strategy to counteract obesity driven PDAC. This will be accomplished by the following specific aims: Aim 1. Determine how adiponectin level effects obesity-induced PDAC progression. In this aim, we will determine whether loss of adiponectin potentiates PDAC progression and whether adiponectin supplementation can counteract the pro-tumorigenic mechanisms of obesity. Aim 2. Determine the effect of SHP-2 inhibition on obesity driven PDAC development and progression. This aim will determine whether loss or inhibition of the tyrosine phosphatase SHP-2 is sufficient to suppress obesity dependent PDAC progression. Aim 3. Determine how adiponectin regulates recruitment of pro-tumorigenic immune cells to the tumor microenvironment. Immune cell profiling will be used to investigate whether adiponectin can block the production and/or secretion of inflammatory chemoattractants from PDAC cells to prevent immune cell recruitment to the tumor microenvironment. The outcome of these specific aims will yield significant new knowledge regarding the mechanisms governing obesity dependent cancer risk and progression. Further, these studies will uncover potential therapeutic uses for adiponectin receptor agonists in PDAC.

肥胖的流行是六种最常见癌症中五种的重要危险因素，包括胰腺导管腺癌（PDAC）。与肥胖相关的炎症反应会导致脂肪分泌细胞因子（称为脂肪因子）的失调。在肥胖个体中，血清水平瘦素（一种促肿瘤脂肪因子）显着增加，而抗肿瘤脂联素水平下降，最终促进癌症进展。我们的努力表明，肥胖会导致脂肪细胞增加瘦素和 IL-6 分泌，在 PDAC 细胞中发挥促肿瘤作用，驱动增殖、迁移和体内肿瘤生长。我们现在已经确定，抗肿瘤脂肪因子脂联素可以抵消促肿瘤脂肪因子通过多种机制对肥胖相关的 PDAC 进展产生影响。首先，脂联素拮抗瘦素和 IL-6 诱导的 PDAC 细胞中 STAT3 和 ERK 信号传导的激活从而抑制 PDAC 的生长。其次，脂联素阻断 Src 同源区 2 的激活含有蛋白酪氨酸磷酸酶 (SHP-2)，瘦素和 IL-6 诱导的 RAF-RAS-ERK 的关键介质发信号。第三，脂联素有效抑制肿瘤细胞分泌炎症细胞引诱剂。我们的结果证实脂联素是肥胖相关 PDAC 进展的关键负调节因子为PDAC的治疗提供了一种新的治疗策略。该提案的目标是确定抵消脂肪分泌细胞因子是否可以抑制 PDAC 进展。我们的中心假设是脂联素通过拮抗 PDAC 来克服先天抵抗脂肪因子通过抑制 SHP-2 和阻止炎症细胞募集介导 RAS 活性进入肿瘤微环境。总体目标是确定脂联素是否代表一种可行的对抗肥胖驱动的 PDAC 的治疗策略。这将通过以下具体目标来实现：目标 1. 确定脂联素水平如何影响肥胖诱导的 PDAC 进展。为了这个目标，我们将确定脂联素的缺失是否会增强 PDAC 的进展以及补充脂联素是否会促进 PDAC 进展可以抵消肥胖的促肿瘤机制。目标 2. 确定 SHP-2 抑制的效果肥胖驱动的 PDAC 发育和进展。这一目标将决定是否丧失或抑制酪氨酸磷酸酶 SHP-2 足以抑制肥胖依赖性 PDAC 进展。目标3。确定脂联素如何调节促肿瘤免疫细胞向肿瘤的募集微环境。免疫细胞分析将用于研究脂联素是否可以阻断 PDAC 细胞产生和/或分泌炎症化学引诱物以阻止免疫细胞招募到肿瘤微环境。这些具体目标的结果将产生重要的新成果关于控制肥胖依赖性癌症风险和进展的机制的知识。此外，这些研究将揭示脂联素受体激动剂在 PDAC 中的潜在治疗用途。