Project 1 – IL-6/STAT3/NF-kB in Adipose-Muscle Crosstalk in the Pancreatic Cancer Macroenvironment

项目 1 — 胰腺癌宏观环境中脂肪-肌肉串扰中的 IL-6/STAT3/NF-kB

• 批准号: 10441211
• 负责人: Teresa A Zimmers
• 金额: $ 37.3万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10441211
• 关键词: Adipocytes; Adipose tissue; Antibodies; Anticachexia Agent; Atrophic; Blood; Blood specimen; Body Weight decreased; Cachexia; Cells; Cessation of life; Chronic; Clinical Data; Clinical Trials; Data; Disease; Fatty acid glycerol esters; Genetic; Genetic Models; Genotype; Human; IL6 gene; Immune; Individual; Inflammation; Interleukin-6; Intervention; Knock-out; Lipids; Lipolysis; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Modeling; Molecular Target; Muscle; Muscle Weakness; Muscle function; Muscular Atrophy; NF-kappa B; Operative Surgical Procedures; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Performance Status; Production; Program Research Project Grants; Proteome; Quality of life; Resolution; Role; STAT3 gene; Severities; Signal Transduction; Skeletal Muscle; Small Nuclear RNA; Source; Specimen; Techniques; Testing; Tissues; Treatment-related toxicity; advanced analytics; cancer cachexia; cancer clinical trial; cancer therapy; chemotherapy; effective therapy; fat wasting; improved; mortality; mouse model; muscle form; novel; pancreatic cancer patients; pancreatic ductal adenocarcinoma model; phase II trial; preclinical study; preservation; programs; reduced muscle mass; response; tocilizumab; treatment response; tumor; tumor microenvironment; tumor progression; uptake; wasting

PROJECT SUMMARY: PROJECT 1 Cancer cachexia, or progressive weight loss featuring immunodysmetabolism, causes ~1/3 of cancer deaths. Loss of muscle mass reduces performance status, predisposes to illness, and increases treatment toxicity while reducing efficacy. Not merely a feature of end-stage cancer, cachexia is a disease with specific, targetable mechanisms. Pre-clinical studies prove that targeting those mechanisms can preserve muscle and lengthen survival, with or without chemotherapy. Cachexia is especially devastating in pancreatic ductal adenocarcinoma (PDAC), afflicting 85% of PDAC patients, most of whom present with weight loss. There is no effective treatment for PDAC and 5-year survival is ~9%. Thus, until PDAC can be cured early in its course, we must manage cachexia, because preserving muscle mass and function will promote response to cancer treatment, improve quality of life, and increase survival. Overall, our Program team hypothesizes that PDAC tumor progression and cachexia is highly orchestrated by an IL-6/IL6R/STAT3/NF-B signaling axis. Project 2 will test NF-B in muscle inflammation and tumor progression, and Project 3 will study IL-6/STAT3/NF-B in tumor-stroma- immune interactions and the macroenvironment. Project 1 of this Program focuses on the crosstalk between adipose and skeletal muscle induced by PDAC tumors, and how IL6R, STAT3, and NF-B combine to produce fat and muscle loss in the PDAC macroenvironment. Abundant data demonstrate that weight loss in PDAC is primarily fat loss in PDAC. Moreover, we showed that fat loss is as predictive of mortality in PDAC as muscle loss, regardless of response to therapy, suggesting a central role for adipose wasting in cachexia. Now we demonstrate that tumor-induced, muscle-derived soluble IL6R appears to induce IL-6 mediated adipocyte lipolysis, products of which feed forward to induce myosteatosis, lipotoxicity, dysmetabolism, weakness and atrophy through a novel PKC-θ to PDK4 axis. Thus, we hypothesize that PDAC induces a feed-forward loop among tumor, fat, and muscle whereby tumor-induced IL-6 and other signals activate adipose STAT3 and lipolysis, products of which are taken up by muscle leading to myosteatosis, PKC-θ activation and subsequent myofiber STAT3, NF-B and PDK4 activation, which promote dysmetabolism, local inflammation and production of soluble IL6R to feed-forward activate adipose wasting. Blocking this cycle will preserve adipose and muscle wasting in PDAC. Using genetic mouse models, human specimens, advanced single cell resolution sequencing as well as correlative cachexia studies in a clinical trial, we will test our hypothesis in these specific aims: AIM 1. Interrogate the mechanisms of adipose-to-muscle crosstalk in the macroenvironment of PDAC cachexia. AIM 2. Interrogate mechanisms of muscle-to-adipose crosstalk in the macroenvironment of PDAC cachexia. AIM 3. Interrogate manifestations and mechanisms of the IL-6/IL6R/STAT3/NF-B pathway in patients with PDAC cachexia.

项目摘要：项目1 癌症恶病质或具有免疫疗法代谢的进行性体重减轻会导致〜1/3的癌症死亡。 肌肉质量的丧失会降低表现状况，易于疾病并增加治疗毒性 降低效率。卡氏症不仅是终阶段癌的特征 机制。临床前研究证明，针对这些机制可以保留肌肉和长度 生存，有或没有化学疗法。恶病质在胰腺导管腺癌中尤其是毁灭性的 （PDAC），折磨了85％的PDAC患者，其中大多数患者体重减轻。没有有效的治疗 对于PDAC，5年生存率约为9％。这，直到PDAC可以在其课程的早期治愈之前，我们必须管理 缓存，因为保留肌肉质量和功能将促进对癌症治疗的反应 生活质量，增加生存。总体而言，我们的计划团队假设PDAC肿瘤进展 Cachexia由IL-6/IL6R/STAT3/NF-B信号轴进行了高度精心策划。项目2将测试NF-B 在肌肉注射和肿瘤进展中，项目3将研究肿瘤 - 细胞瘤中的IL-6/STAT3/NF-B- 免疫相互作用和宏观环境。该计划的项目1重点介绍 PDAC肿瘤诱导的脂肪和骨骼肌，以及IL6R，STAT3和NF-B合并如何产生 PDAC宏观环境中的脂肪和肌肉损失。大量数据表明，PDAC中的体重减轻为 PDAC的主要脂肪损失。此外，我们表明脂肪流失与PDAC的死亡率一样，与肌肉一样 损失，无论对治疗的反应如何，都表明脂肪在卡氏症中的核心作用。现在我们 证明肿瘤诱导的肌肉衍生的固体IL6R似乎诱导IL-6介导的脂肪细胞 脂解，其产物向前诱导肌萎缩症，脂肪毒性，非代谢，虚弱和 通过新颖的PKC-θ到PDK4轴的萎缩。那就是我们假设PDAC诱导馈送前循环 在肿瘤，脂肪和肌肉中，肿瘤诱导的IL-6和其他信号激活脂肪Stat3和 脂解，其产物被肌肉吸收，导致肌萎缩症，PKC-θ激活和随后的序列 Myofiber Stat3，NF-B和PDK4激活，促进替代替代代谢，局部注射和生产 固体IL6R的馈送激活脂肪浪费。阻止此周期将保留脂肪和肌肉 在PDAC浪费。使用遗传小鼠模型，人类标本，高级单细胞分辨率测序 除临床试验中的相关缓存研究外，我们还将在这些特定目的中检验我们的假设： 目标1。询问PDAC宏观环境中脂肪到肌肉串扰的机制 卡希克西亚。 AIM 2。审问PDAC宏观环境中的肌肉到辅助串扰的机制 卡希克西亚。 AIM 3。患者的IL-6/IL6R/STAT3/NF-B途径的询问表现和机制 与PDAC Cachexia。