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.

项目总结：总体 该计划项目的总体目标是更好地了解 导致癌症患者恶病质，特别是胰腺导管腺癌(PDAC)患者 在所有肿瘤类型中，恶病质的发生率最高。失去5%的癌症患者 他们病前体重的一半被认为是恶病质。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，在这个人群中，体重任何减少10%都会导致 为了更差的生存。虽然PDAC已经做了一些改进以延长5年存活率， 这仍然是所有实体肿瘤中发病率最低的之一。因此，在发现治疗方法有效治疗之前， 了解恶病质的原因对于改善治疗反应、生活质量和 潜在的整体生存。我们计划项目的主要创新理念是相信有效的 治疗PDAC诱发的恶病质必须考虑本综合征的大环境，以便治疗 肿瘤与周围组织的损耗同时发生。我们在本计划中关注的效应器 项目是NF-B/IL-6/STAT3信号轴的一部分。我们的假设是，NF-B/IL-6/STAT3 在PDAC诱导的恶病质中，信号轴是大环境的中枢调节因子。这一假说将 在4核支持下，在3个项目中进行测试。项目1侧重于IL-6/STAT3部分的核因子- B/IL-6/STAT3信号轴。具体来说，研究将确定IL-6和IL-6受体的参与 通过STAT3调节脂肪和肌肉的流失。项目2的重点是信号轴内的核因子-B， 探索肌肉干细胞中核因子-B促进局部肌肉功能的两个新概念 炎症和PDAC进展通过调节先天免疫细胞和获得性免疫细胞的监视。 项目3将探索基质成纤维细胞中的IL-6/STAT3轴。具体地说，STAT3信号是如何进入 肿瘤和周围组织中的间质间充质细胞产生免疫抑制 有利于PDAC进展和癌症恶病质的大环境。核心甲(行政)将提供 计划组织的管理结构。核心B(人类生物群落)将保持一个 来自患有和不伴有恶病质的PDAC患者的组织信息库，并支持下一代测序 分析。CORE C(免疫表型)将提供scRNA-Seq和多光谱成像方面的专业知识 PDAC诱导恶病质中的肿瘤、骨骼肌和脂肪。核心D(生物统计学)将提供生物统计学 支持。该计划包含基于NCI之间的协作的多个集成点 南卡罗来纳医科大学和印第安纳大学指定的癌症中心及其 各自的癌症恶病质项目。从这些研究中获得的结果将推动我们的基本 了解肿瘤-肌肉/脂肪在PDAC大环境中的相互作用可能适用 与恶病质导致患者发病率和死亡率有关的其他癌症疾病。