Tumor tissue crosstalk in the macroenvironment of pancreatic cancer cachexia

胰腺癌恶病质大环境中的肿瘤组织串扰

• 批准号: 10425256
• 负责人: Teresa A Zimmers
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10425256
• 关键词: Activities of Daily Living; Adipocytes; Adipose tissue; Anticachexia Agent; Biological Markers; Blood; Body Composition; Body Weight decreased; Body of pancreas; Cachexia; Cessation of life; Chemotherapy-Oncologic Procedure; Clinical; Clinical Data; Clinical Trials; Data; Distant; Environment; Fatty acid glycerol esters; Female; Future; Gene Expression; Genes; Hematopoietic System; Heterogeneity; Hospitals; Human; Immune response; Implant; Individual; Inflammation; Interleukin 6 Receptor; Interleukin-6; Life; Link; Lipolysis; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Metabolism; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Mus; Muscle; Muscular Atrophy; NF-kappa B; Nervous system structure; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathogenesis; Pathway interactions; Patients; Phenotype; Process; Production; Proteomics; Resources; Rodent; STAT3 gene; Sampling; Sex Differences; Signal Transduction; Skeletal Muscle; Specimen; Stress; Testing; Therapeutic; Tissues; Translations; Treatment-related toxicity; Tumor Tissue; Tumor-Derived; Validation; Xenograft procedure; biobank; body system; cancer cachexia; chemotherapy; cohort; experience; feeding; genetic signature; human tissue; implantation; male; molecular phenotype; morphometry; mortality; mouse model; novel; pancreatic cancer patients; patient subsets; phenotypic data; pre-clinical; preclinical study; preservation; prevent; sex; therapeutic evaluation; trait; transcriptome sequencing; tumor; wasting

Progressive weight loss also known as cancer cachexia, afflicts ~85% of patients with pancreatic ductal adenocarcinoma (PDAC). Cachexia associates with treatment toxicity, morbidity, and mortality, contributing to the 91% 5-year mortality among patients with PDAC. Moreover, while most patients with PDAC die with cachexia, we posit that many or most die of cachexia. Currently there are no approved treatments for cachexia, although pre-clinical studies demonstrate that preserving fat and muscle can prolong function and life with and without chemotherapy. Here we show a novel pathway linking tumor, adipose, and muscle. We show that PDAC tumors express Interleukin-6 (IL-6), which circulates to fat, causing local inflammation and further secretion of IL-6. IL-6 also circulates to muscle, inducing feed-forward production of IL-6 and shedding of the IL-6 receptor (sIL6R). Muscle-derived IL6R circulates to fat, initiating trans-signaling and adipocyte lipolysis. Products of lipolysis are taken up by skeletal muscle, leading to myosteatosis, lipotoxic stress, and muscle atrophy. Inhibition of tumor IL-6 reduces adipose wasting and prevents muscle loss, demonstrating a key role for IL-6 in the PDAC macro-environment. Preliminary data from patients shows IL-6 expression in tumors, identifies IL-6 as an upstream regulator in blood, demonstrates IL-6 and IL-6R in adipose tissue, and documents a STAT3/NF-kB gene signature in muscle. However, only a subset of patients showed elevated IL- 6 pathway activation, whereas 85% of patients experience cachexia. This suggests that IL-6-induced inflammation might be a driver in a subset of patients, potentially linked to tumor production of IL-6. Indeed, our preliminary data using orthotopic xenografts of human tumors in mice indicates that patient tumors have differing intrinsic abilities to cause cachexia, which might be related to IL-6 expression from the tumor. Here we will interrogate human tissue specimens to document the diversity in the cachexia phenotype and to identify patients with IL-6 pathway activity. As well, we will as use patient-derived orthotopic xenografts in mouse models to evaluate the intrinsic ability of tumors to cause cachexia and the therapeutic potential of blocking IL- 6 trans-signaling and tissue crosstalk. To do so we will leverage our existing cachexia biorepository and our lines of PDAC cachexia “avatars”—mice implanted with human tumor fragments. AIM 1: Interrogate phenotypic and molecular heterogeneity and tumor-tissue crosstalk in biospecimens from patients with well characterized body composition and pancreatic cancer cachexia. AIM 2: Evaluate functional heterogeneity in the capacity of individual tumors to cause cachexia AIM 3: Test the importance of tumor-tissue crosstalk via IL-6 trans-signaling and lipolysis in a pre-clinical mouse hospital setting.

进行性体重减轻也称为癌症恶病质，肿瘤约85％的胰腺导管患者 腺癌（PDAC）。恶病质与治疗毒性，发病率和死亡率相关，有助于 PDAC患者的5年死亡率为91％。而且，大多数PDAC患者死于 卡希克西亚，我们的海报是许多或大多数死亡的死亡病毒。目前尚无批准的恶病质治疗方法 尽管临床前研究表明，保存脂肪和肌肉可以延长和寿命，并使用 没有化​​学疗法。在这里，我们显示了一条新的途径，将肿瘤，脂肪和肌肉联系起来。我们表明 PDAC肿瘤表达白细胞介素6（IL-6），该肿瘤圆满脂肪，导致局部炎症并进一步 分泌IL-6。 IL-6还循环到肌肉，诱导IL-6的前馈产生和脱落 IL-6受体（SIL6R）。肌肉衍生的IL6R圆向脂肪，启动的反式信号和脂肪细胞脂解。 脂解的产物被骨骼肌吸收，导致肌萎缩症，脂肪毒性应激和肌肉 萎缩。抑制肿瘤IL-6减少脂肪浪费并防止肌肉损失，这表明了关键作用 用于PDAC宏观环境中的IL-6。来自患者的初步数据显示肿瘤中的IL-6表达， 将IL-6鉴定为血液中上游调节剂，在脂肪组织中证明IL-6和IL-6R，以及 记录肌肉中的STAT3/NF-KB基因签名。但是，只有一部分患者显示了IL- 6个途径激活，而85％的患者患有恶病质。这表明IL-6引起 炎症可能是一部分患者的驱动力，可能与IL-6的肿瘤产生有关。确实，我们的 使用小鼠人类肿瘤的原位异种移植的初步数据表明患者肿瘤具有 区分固有能力以引起恶病质，这可能与肿瘤的IL-6表达有关。这里 我们将询问人体组织标本，以记录恶病质表型的多样性并确定 IL-6途径活性的患者。同样，我们将在鼠标中使用患者来源的原位异种移植物 评估肿瘤引起恶病质和阻断IL-的治疗潜力的固有能力的模型 6个反式信号和组织串扰。为此，我们将利用我们现有的Cachexia Biorepository和我们的 PDAC Cachexia的线“化身” - 植入人类肿瘤碎片的裂体。 AIM 1：从生物测量中审问表型和分子异质性以及肿瘤组织串扰 人体成分和胰腺癌恶病质的患者。 目标2：评估单个肿瘤能力的功能异质性引起恶病质 AIM 3：通过IL-6反式信号和脂解测试肿瘤组织串扰的重要性 鼠标医院设置。