Tumor tissue crosstalk in the macroenvironment of pancreatic cancer cachexia

进行性体重减轻也称为癌症恶病质，约85%的胰腺导管患者患有该病 腺癌(PDAC)。恶病质与治疗毒性、发病率和死亡率有关，导致 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，我们假设许多人或大多数人死于恶病质。目前还没有被批准的治疗恶病质的方法， 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 没有化疗的话。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肿瘤表达白介素6(IL-6)，它循环到脂肪，引起局部炎症和进一步 IL-6的分泌。IL-6还循环到肌肉，诱导前馈产生IL-6，并使 白介素6受体(SIL6R)。肌肉来源的IL6R循环到脂肪，启动反式信号转导和脂肪细胞脂解。 脂肪分解的产物被骨骼肌摄取，导致肌肉骨质瘤、脂肪毒性应激和肌肉。 萎缩。抑制肿瘤IL-6减少脂肪消耗和防止肌肉损失，显示出关键作用 用于PDAC宏观环境中的IL-6。来自患者的初步数据显示，IL-6在肿瘤中表达， 确定IL-6是血液中的上游调节因子，在脂肪组织中显示IL-6和IL-6R，以及 记录了肌肉中的STAT3/NF-kB基因签名。然而，只有一小部分患者表现出IL-1升高 6通路激活，而85%的患者出现恶病质。这表明IL-6诱导的 炎症可能是部分患者的驱动因素，可能与肿瘤产生IL-6有关。的确，我们的 使用小鼠人肿瘤原位移植的初步数据表明，患者肿瘤 导致恶病质的内在能力不同，这可能与肿瘤中IL-6的表达有关。这里 我们将询问人类组织样本，以记录恶病质表型的多样性，并确定 IL-6途径活跃的患者。此外，我们还将在小鼠身上使用患者来源的异种原位移植。 评估肿瘤引起恶病质的内在能力和阻断IL-2治疗潜力的模型 6转导和组织串扰。为此，我们将利用我们现有的恶病质生物资源库和我们的 PDAC恶病质“化身”--植入人类肿瘤碎片的小鼠。 目的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。 身体成分特征良好的患者，胰腺癌恶病质。 目的2：评估单个肿瘤引起恶病质的功能异质性 目的3：在一项临床前研究中，测试通过IL-6转导信号和脂解作用的肿瘤-组织串扰的重要性 老鼠医院环境。

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.