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形式的癌症中的五个，包括胰腺导管腺癌（PDAC）。与肥胖相关的炎症反应导致脂肪分泌细胞因子的失调，称为脂肪因子。在肥胖的个体中，血清水平瘦素是一种促肿瘤脂肪因子，大幅增加，而抗肿瘤脂联素水平降低，最终促进癌症的进展。我们的努力表明，肥胖会诱导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。现在，我们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在肥胖中通过多种机制与PDAC进展相关的影响。首先，脂联素拮抗瘦素和IL-6诱导的PDAC细胞中Stat3和ERK信号的激活导致抑制PDAC生长。其次，脂联素阻断SRC同源性区域2的激活含有蛋白酪氨酸磷酸酶（SHP-2），这是瘦素和IL-6诱导的RAF-RAS-ERK的关键介体信号。第三，脂联素有效抑制炎症细胞吸引肿瘤细胞的分泌。我们的结果证明脂联素是肥胖相关的PDAC进展和为PDAC治疗提供了一种新型的治疗策略。该提案的目的是确定抵消脂肪分泌的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对抗克服了PDAC的先天抵抗力脂肪因子通过抑制SHP-2并通过阻断炎症细胞募集来介导的RAS活性进入肿瘤微环境。总体目的是确定脂联素是否代表可行应对肥胖驱动PDAC的治疗策略。这将通过以下特定目的来完成：目标1。确定脂联素水平如何影响肥胖诱导的PDAC进展。在这个目标中，我们将确定脂联素的丧失是否增强PDAC的进展以及是否补充脂联素可以抵消肥胖的促肿瘤机制。 AIM 2。确定SHP-2抑制作用关于肥胖驱动PDAC的发展和进展。这个目标将决定损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的免疫细胞募集到肿瘤微环境。免疫细胞分析将用于研究脂联素是否可以阻止从PDAC细胞中产生和/或分泌炎症性趋化剂，以防止免疫细胞招募肿瘤微环境。这些特定目标的结果将产生重要的新关于依赖肥胖的癌症风险和进展的机制的知识。此外，这些研究将发现PDAC中脂联素受体激动剂的潜在治疗用途。