The role of the macroenvironment in pancreatic cancer-induced cachexia

大环境在胰腺癌引起的恶病质中的作用

• 批准号: 10441210
• 负责人: Denis C Guttridge
• 金额: $ 196.24万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10441210
• 关键词: Adipose tissue; Anticachexia Agent; Belief; Biological Markers; Biometry; Body Weight; Body Weight decreased; Cachexia; Cancer Patient; Cells; Cessation of life; Collaborations; Communities; Data; Dietary Intervention; Exhibits; Fatigue; Fatty acid glycerol esters; Fibroblasts; Future; Goals; Human; Immune; Immunophenotyping; Incidence; Indiana; Inflammation; Interleukin 6 Receptor; Interleukin-6; Literature; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Medical; Mesenchymal; Modeling; Molecular; Morbidity - disease rate; Muscle; Muscle satellite cell; Muscular Atrophy; Myomatous neoplasm; NCI-Designated Cancer Center; Organization administrative structures; Outcome; Pancreatic Ductal Adenocarcinoma; Patients; Peripheral; Population; Prognosis; Publishing; Quality of life; Resources; Role; STAT3 gene; Sampling; Signal Pathway; Signal Transduction; Skeletal Muscle; Solid Neoplasm; South Carolina; Survival Rate; Syndrome; Testing; Therapeutic; Thinness; Time; Tissue Banks; Tissues; Translating; Tumor Burden; Universities; Weight; Weight Gain; bone imaging; cancer cachexia; cancer imaging; combat; effective therapy; improved; improved outcome; innovation; insight; mortality; mouse model; next generation sequencing; novel; preclinical study; programs; single-cell RNA sequencing; standard of care; therapeutic target; treatment response; tumor; tumor microenvironment; tumor progression; wasting

PROJECT SUMMARY: OVERALL The overall goal of this Program Project is to gain a better understanding of the underlying mechanisms that drive cachexia in cancer patients, especially patients with pancreatic ductal adenocarcinoma (PDAC) that exhibit one of the highest incidences of cachexia among all tumor types. Cancer patients who have lost > 5% of their pre-illness weight are considered cachectic. In comparison, 85% of PDAC patients lose an average of 14% body weight, and recent published data show that any loss of body weight > 10% in this population leads to poorer survival. Although some improvements have been made in PDAC to extend the 5-year survival rate, this is still among the lowest rate of all solid tumors. Thus, until therapeutics are found to effectively treat PDAC, understanding the causes of cachexia is vital to improving treatment responses, quality of life, and potentially overall survival. The main innovative concept in our Program Project is the belief that to effective treat PDAC-induced cachexia one must consider the macroenvironment of this syndrome, so as to treat the tumor and the wasting of peripheral tissues at the same time. The effectors we focus on in this Program Project are part of the NF-B/IL-6/STAT3 signaling axis. Our hypothesize is that the NF-B/IL-6/STAT3 signaling axis is a central regulator of the macroenvironment in PDAC-induced cachexia. This hypothesis will be tested in 3 Projects under the support of 4 Cores. Project 1 focuses on the IL-6/STAT3 portion of the NF- B/IL-6/STAT3 signaling axis. Specifically, studies will define the participation of IL-6 and the IL-6 receptor acting through STAT3 to mediate fat and muscle loss. Project 2 focuses on NF-B within the signaling axis, exploring two fresh concepts in how NF-B functions in muscle stem cells to promote local muscle inflammation and in PDAC progression by modulating the surveillance of innate and adaptive immune cells. Project 3 will explore the IL-6/STAT3 axis within stroma fibroblasts. Specifically, how STAT3 signaling in stromal mesenchymal cells in the tumor and peripheral tissues produces an immunosuppressive macroenvironment that favors PDAC progression and cancer cachexia. Core A (Administration) will provide administrative structure for the organization of the program. Core B (Human Biospecimens) will maintain a repository of tissues from PDAC patients with and without cachexia and support next generation sequencing analysis. Core C (Immunophenotyping) will provide expertise in scRNA-Seq and multispectral imaging of the tumor, skeletal muscle, and fat in PDAC-induced cachexia. Core D (Biostatistics) will provide biostatistical support. This Program contains multiple points of integration founded on collaborations between NCI designated Cancers Centers at the Medical University of South Carolina and Indiana University and their respective Cancer Cachexia Programs. The outcome obtained from these studies will advance our basic understanding of tumor-muscle/fat interactions within a PDAC macroenvironment that will likely apply to other cancer conditions where cachexia contributes to the morbidity and mortality of patients.

项目概要：总体 本计划项目的总体目标是更好地了解 导致癌症患者出现恶病质，尤其是胰腺导管腺癌（PDAC）患者， 在所有肿瘤类型中表现出恶病质的最高发病率之一。癌症患者死亡率> 5% 患病前体重的百分之二十被认为是恶病质。相比之下，85%的PDAC患者平均损失 14%的体重，最近公布的数据表明，在这个群体中，任何体重减轻> 10%的情况都会导致 更差的生存。虽然PDAC已经取得了一些改进，以延长5年生存率， 这仍然是所有实体瘤中发病率最低的。因此，在找到有效治疗 PDAC，了解恶病质的原因是至关重要的，以改善治疗反应，生活质量， 潜在的总体生存率。在我们的计划项目的主要创新理念是相信，以有效的 治疗PDAC引起的恶病质必须考虑这种综合征的大环境，以便治疗 肿瘤和周围组织的浪费。我们在本计划中关注的效应器 项目是NF-κ B B/IL-6/STAT 3信号传导轴的一部分。我们的假设是NF-κ B B/IL-6/STAT 3在细胞内表达， 信号传导轴是PDAC诱导的恶病质中宏观环境的中心调节因子。这一假设将 在4个核心的支持下，在3个项目中进行测试。项目1关注NF-κ B的IL-6/STAT 3部分， IL B/IL-6/STAT 3信号轴。具体来说，研究将确定IL-6和IL-6受体的参与， 通过STAT 3介导脂肪和肌肉损失。项目2关注信号传导轴内的NF-κ B B， 探索NF-κ B B在肌肉干细胞中如何发挥作用以促进局部肌肉的两个新概念 通过调节先天性和适应性免疫细胞的监视，在炎症和PDAC进展中起作用。 项目3将探索基质成纤维细胞内的IL-6/STAT 3轴。具体来说，STAT 3信号如何在 肿瘤和周围组织中的间质细胞产生免疫抑制性免疫抑制剂， 这是一种有利于PDAC进展和癌症恶病质的宏观环境。核心A（行政）将提供 组织方案的行政结构。核心B（人类生物标本）将保持 来自具有和不具有恶病质的PDAC患者的组织库，并支持下一代测序 分析.核心C（免疫表型）将提供scRNA-Seq和多光谱成像的专业知识， PDAC诱导的恶病质中的肿瘤、骨骼肌和脂肪。核心D（生物统计）将提供生物统计 支持.该计划包含多个基于NCI之间合作的集成点 南卡罗来纳州和印第安纳州大学的指定癌症中心及其 癌症恶病质项目。从这些研究中获得的结果将促进我们的基本 了解PDAC宏观环境中肿瘤-肌肉/脂肪相互作用， 恶病质导致患者发病率和死亡率的其他癌症病症。