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: 10172469
• 负责人: Teresa A Zimmers
• 金额: $ 39.88万
• 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/10172469
• 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; 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 癌症恶病质或以免疫代谢异常为特征的进行性体重减轻导致约 1/3 的癌症死亡。 肌肉质量的损失会降低体能状态，容易患病，并增加治疗毒性 降低疗效不仅仅是终末期癌症的一个特征，恶病质也是一种具有特异性、可针对性的疾病。 临床前研究证明，针对这些机制可以保护肌肉并延长肌肉。 无论有或没有化疗，恶病质对胰腺导管腺癌的生存尤其具有破坏性。 (PDAC)，困扰 85% 的 PDAC 患者，其中大多数表现为体重减轻，目前尚无有效的治疗方法。 PDAC 的 5 年生存率约为 9%，因此，在 PDAC 能够早期治愈之前，我们必须进行管理。 恶病质，因为保留肌肉质量和功能将促进对癌症治疗的反应，改善 总体而言，我们的项目团队推进了 PDAC 肿瘤的进展。 恶病质是由 IL-6/IL6R/STAT3/NF-β 信号轴高度协调的。项目 2 将测试 NF-βB。 肌肉炎症和肿瘤进展，项目 3 将研究肿瘤间质中的 IL-6/STAT3/NF-κB 该计划的项目 1 重点研究免疫相互作用和宏观环境之间的串扰。 PDAC 肿瘤诱导的脂肪和骨骼肌，以及 IL6R、STAT3 和 NF-κB 如何结合产生 PDAC 宏观环境中的脂肪和肌肉减少 大量数据表明，PDAC 中的体重减轻是显着的。 主要是 PDAC 中的脂肪减少，此外，我们发现脂肪减少与肌肉减少一样可以预测 PDAC 的死亡率。 无论对治疗的反应如何，脂肪消耗都表明脂肪消耗在恶病质中起着核心作用。 证明肿瘤诱导的、肌肉来源的可溶性 IL6R 似乎可以诱导 IL-6 介导的脂肪细胞 脂肪分解，其产物向前诱导肌脂肪变性、脂毒性、代谢障碍、虚弱和 通过新的 PKC-θ 到 PDK4 轴的萎缩因此，我们追踪 PDAC 诱导前馈循环。 在肿瘤、脂肪和肌肉之间，肿瘤诱导的 IL-6 和其他信号激活脂肪 STAT3 和 脂肪分解，其产物被肌肉吸收，导致肌脂肪变性、PKC-θ 激活以及随后的 肌纤维 STAT3、NF-κB 和 PDK4 激活，促进代谢障碍、局部炎症和生产 可溶性 IL6R 的前馈激活脂肪消耗，阻断该循环将保护脂肪和肌肉。 使用基因小鼠模型、人类样本、先进的单细胞分辨率测序来检测消瘦。 以及临床试验中的相关恶病质研究，我们将在以下特定目标中检验我们的假设： 目的 1. 探究 PDAC 宏观环境中脂肪与肌肉串扰的机制 恶病质。 目标 2. 探究 PDAC 宏观环境中肌肉与脂肪串扰的机制 恶病质。 AIM 3. 探究患者IL-6/IL6R/STAT3/NF-κB通路的表现和机制 患有 PDAC 恶病质。