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: 10634573
• 负责人: Denis C Guttridge
• 金额: $ 195.72万
• 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/10634573
• 关键词: Acceleration; 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; spectrograph; 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.

项目摘要：总体 该计划项目的总体目标是更好地了解 在癌症患者中驱动恶病质，尤其是患有胰腺导管腺癌（PDAC）的患者 在所有肿瘤类型中，表现出卡希克西的最高发病率之一。损失> 5％的癌症患者 它们的罚球前重量被认为是化学的。相比之下，有85％的PDAC患者平均失去 体重14％，最近发表的数据表明，该人群中的任何体重损失> 10％。 生存较差。尽管PDAC已进行了一些改进以延长5年的生存率，但 这仍然是所有实体瘤中最低的速率之一。直到发现治疗有效治疗 PDAC，了解恶病质的原因对于改善治疗反应，生活质量和 潜在的总体生存。我们计划项目中的主要创新概念是相信有效的 治疗PDAC诱导的卡希克西亚必须考虑该综合征的宏观环境，以便治疗 肿瘤和外周组织浪费。我们在该计划中关注的效果 项目是NF-B/IL-6/STAT3信号轴的一部分。我们假设的是NF-B/IL-6/STAT3 信号轴是PDAC诱导的缓存中宏观环境的中心调节因子。这个假设将会 在4个核心的支持下在3个项目中进行测试。项目1专注于NF-的IL-6/STAT3部分 B/IL-6/STAT3信号轴。具体而言，研究将定义IL-6和IL-6接收器的参与 通过STAT3作用以介导脂肪和肌肉损失。项目2专注于信号轴内的NF-B， 探索NF-b如何在肌肉干细胞中发挥作用以促进局部肌肉的两个新鲜概念 通过调节先天性和适应性免疫球的监视，炎症和PDAC进展。 项目3将探索基质成纤维细胞内的IL-6/STAT3轴。具体而言，STAT3在 肿瘤和周围组织中的基质间充质细胞会产生免疫抑制 有利于PDAC进展和癌症恶病质的宏观环境。核心A（管理）将提供 该计划组织的行政结构。核B（人类生物测量）将保持 PDAC患者有和没有恶病质的PDAC患者的组织存储库，并支持下一代测序 分析。 Core C（免疫表型）将在SCRNA-SEQ和多光谱成像方面提供专业知识 PDAC诱导的恶病质中的肿瘤，骨骼肌和脂肪。核心D（生物统计学）将提供生物统计学 支持。该程序包含基于NCI之间的协作的多个集成点 南卡罗来纳州医科大学和印第安纳大学及其指定的癌症中心及其 各自的癌症恶病质计划。从这些研究中获得的结果将推动我们的基本 了解可能适用的PDAC宏观环境中肿瘤肌肉/脂肪相互作用 在其他恶病质有助于患者的发病率和死亡率的其他癌症状况下。

项目成果

Bilateral Renal Auto-Transplantation for Retroperitoneal Sarcomas: Is It Underutilized?

• DOI: 10.3390/curroncol30080552
• 发表时间: 2023-08-14
• 期刊: CURRENT ONCOLOGY
• 影响因子: 2.6
• 作者: Robinson, Tyler P.;Milgrom, Daniel P.;Nagaraju, Santosh;Goggins, William C.;Samy, Kannan P.;Koniaris, Leonidas G.
• 通讯作者: Koniaris, Leonidas G.

The impact of inflammation and acute phase activation in cancer cachexia.

• DOI: 10.3389/fimmu.2023.1207746
• 发表时间: 2023
• 期刊: Frontiers in immunology
• 影响因子: 7.3