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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

基本信息

批准号：
10704535
负责人：
Teresa A Zimmers
金额：
--
依托单位：
PORTLAND VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10704535
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 Trials Data Distant 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 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 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

项目摘要

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，约85%的胰腺导管癌患者患有这种疾病。腺癌（PDAC）。恶病质与治疗毒性、发病率和死亡率相关， PDAC患者的5年死亡率为91%。此外，虽然大多数PDAC患者死于恶病质，我们认为很多或大多数死于恶病质。目前还没有批准的恶病质治疗方法，尽管临床前研究表明，保留脂肪和肌肉可以延长功能和寿命，没有化疗。在这里，我们展示了一种连接肿瘤、脂肪和肌肉的新途径。我们证明了 PDAC肿瘤表达白细胞介素-6（IL-6），其循环至脂肪，引起局部炎症，并进一步 IL-6的分泌。IL-6还循环到肌肉，诱导IL-6的前馈产生和细胞因子的脱落。 IL-6受体（sIL 6 R）。肌肉来源的IL 6 R循环至脂肪，启动反式信号传导和脂肪细胞脂解。脂肪分解的产物被骨骼肌吸收，导致肌肉脂肪变性、脂毒性应激和肌肉萎缩。萎缩抑制肿瘤IL-6可减少脂肪消耗并防止肌肉损失，显示出关键作用 PDAC宏环境中的IL-6。来自患者的初步数据显示肿瘤中的IL-6表达，鉴定IL-6作为血液中的上游调节因子，证明脂肪组织中的IL-6和IL-6 R，记录了肌肉中的STAT 3/NF-kB基因签名。然而，只有一部分患者的IL-10水平升高， 6通路激活，而85%的患者经历恶病质。这表明IL-6诱导的炎症可能是患者亚组的驱动因素，可能与肿瘤产生IL-6有关。的确，我们的在小鼠中使用人肿瘤的原位异种移植物的初步数据表明，导致恶病质的不同内在能力，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， IL-6通路活性的患者。同样，我们将在小鼠中使用患者来源的原位异种移植物，模型来评估肿瘤引起恶病质的内在能力和阻断IL-10的治疗潜力。 6跨信号传导和组织串扰。为此，我们将利用现有的恶病质生物储存库和 PDAC恶病质“化身”-植入人类肿瘤碎片的小鼠。目的1：询问生物标本中的表型和分子异质性以及肿瘤-组织串扰，具有良好特征的身体组成和胰腺癌恶病质的患者。目的2：评价个体肿瘤引起恶病质能力的功能异质性目的3：在临床前研究中，通过IL-6反式信号转导和脂解来测试肿瘤-组织串扰的重要性。鼠标医院设置。