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

项目概要：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。 肌肉质量的损失降低了性能状态，易患病，并增加了治疗毒性， 降低功效。恶病质不仅仅是终末期癌症的一个特征， 机制等临床前研究证明，针对这些机制可以保护肌肉， 生存率，有或没有化疗。恶病质在胰腺导管腺癌中尤其具有破坏性 （PDAC），困扰85%的PDAC患者，其中大多数人体重减轻。尚无有效的治疗方法 PDAC和5年生存率约为9%。因此，直到PDAC可以治愈早期的过程中，我们必须管理 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 提高生活质量，提高生存率。总的来说，我们的项目团队假设PDAC肿瘤进展 恶病质是由IL-6/IL 6 R/STAT3/NF-κ B B信号轴高度协调的。项目2将测试NF-κ B B 在肌肉炎症和肿瘤进展中，项目3将研究肿瘤间质中的IL-6/STAT3/NF-κ B B， 免疫相互作用和宏观环境。本计划的项目1侧重于 PDAC肿瘤诱导的脂肪和骨骼肌，以及IL 6 R、STAT 3和NF-κ B B联合收割机如何结合产生 脂肪和肌肉损失在PDAC宏环境。大量数据表明，PDAC中的体重减轻是 主要是PDAC中的脂肪损失。此外，我们发现，脂肪损失是预测死亡率在PDAC作为肌肉 无论对治疗的反应如何，脂肪减少都表明脂肪消耗在恶病质中的核心作用。现在我们 表明肿瘤诱导的、肌肉来源的可溶性IL-6 R似乎诱导IL-6介导的脂肪细胞 脂肪分解，其产物前馈诱导肌脂肪变性、脂毒性、代谢异常、虚弱和 通过新的PKC-θ至PDK4轴的萎缩。因此，我们假设PDAC诱导前馈回路 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， 脂肪分解，其产物被肌肉吸收，导致肌肉脂肪变性、PKC-θ激活和随后的 肌纤维STAT3、NF-κ B B和PDK 4活化，其促进代谢异常、局部炎症和产生 可溶性IL-6R的水平来前馈激活脂肪消耗。阻止这个循环将保留脂肪和肌肉 在PDAC中浪费。使用遗传小鼠模型，人类标本，先进的单细胞分辨率测序 以及临床试验中的相关恶病质研究，我们将在这些特定目标中检验我们的假设： AIM 1.在PDAC的宏观环境中探究脂肪-肌肉串扰的机制 恶病质 AIM 2. PDAC宏环境中肌肉-脂肪串扰的机制探讨 恶病质 AIM 3. IL-6/IL 6 R/STAT3/NF-κ B B通路在肺癌患者中的表现及机制探讨 PDAC恶病质

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.