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.

渐进性体重减轻也称为癌症恶病质，约 85% 的胰腺导管癌患者受到影响 腺癌 (PDAC) 与治疗毒性、发病率和死亡率相关，导致 此外，PDAC 患者的 5 年死亡率为 91%，而大多数 PDAC 患者死于此病。 恶病质，我们发现许多或大多数人死于恶病质，目前还没有批准用于恶病质的治疗方法， 尽管临床前研究表明，保存脂肪和肌肉可以延长功能和寿命 在这里，我们展示了一种连接肿瘤、脂肪和肌肉的新途径。 PDAC 肿瘤表达白细胞介素 6 (IL-6)，它会分解脂肪，导致局部炎症并进一步 IL-6 的分泌也会对肌肉产生影响，诱导 IL-6 的前馈产生和脱落。 IL-6 受体 (sIL6R)。肌肉来源的 IL6R 会破坏脂肪，启动反式信号传导和脂肪细胞脂肪分解。 脂肪分解产物被骨骼肌吸收，导致肌脂肪变性、脂毒性应激和肌肉损伤 抑制肿瘤 IL-6 可减少脂肪消耗并防止肌肉损失，这表明其具有关键作用。 PDAC宏观环境中的IL-6 来自患者的初步数据显示肿瘤中IL-6的表达， 确定 IL-6 是血液中的上游调节因子，证明脂肪组织中的 IL-6 和 IL-6R，以及 记录了肌肉中的 STAT3/NF-kB 基因特征，然而，只有一部分患者表现出 IL-升高。 6 激活途径，而 85% 的患者出现恶病质，这表明 IL-6 诱导。 炎症可能是一部分患者的驱动因素，可能与肿瘤产生 IL-6 有关。 在小鼠体内使用人类肿瘤原位异种移植物的初步数据表明，患者肿瘤已 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。 我们将研究人体组织标本以记录恶病质表型的多样性并识别 此外，我们还将在小鼠中使用患者来源的原位异种移植物。 评估肿瘤引起恶病质的内在能力以及阻断 IL-2 的治疗潜力的模型 6 转信号和组织串扰为此，我们将利用我们现有的恶病质生物库和我们的技术。 PDAC 恶病质“化身”系列——植入人类肿瘤碎片的小鼠。 目标 1：询问生物样本中的表型和分子异质性以及肿瘤组织串扰 具有明确的身体成分和胰腺癌恶病质的患者。 目标 2：评估个体肿瘤引起恶病质能力的功能异质性 目标 3：在临床前测试中通过 IL-6 反式信号传导和脂肪分解测试肿瘤组织串扰的重要性 老鼠医院环境。