Delineating the contribution of muscle wasting to tumor progression

描述肌肉萎缩对肿瘤进展的贡献

• 批准号: 10824840
• 负责人: Jason Doles
• 金额: $ 38.36万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10824840
• 关键词: Adipose tissue; Advanced Malignant Neoplasm; Affect; Alanine; Atrophic; Attenuated; Biochemistry; Cachexia; Cancer Etiology; Cancer Patient; Cell physiology; Cells; Clinical; Complex; Consumption; Cues; Data; Development; Energy Metabolism; Evolution; Exhibits; Gene Expression; Genetically Engineered Mouse; Gluconeogenesis; Glucose; Goals; Growth; Immune response; Intervention; Liver; Malignant Neoplasms; Molecular; Molecular Biology; Molecular Target; Morbidity - disease rate; Mus; Muscle; Muscle function; Muscular Atrophy; Neoplasm Transplantation; Oncology; Operative Surgical Procedures; Patient-Focused Outcomes; Patients; Phenotype; Play; Prevention; Production; Prognosis; Proteins; Protocols documentation; Quality of life; Reproducibility; Resistance; Rest; Role; Skeletal Muscle; Syndrome; Therapeutic Intervention; Time; Tissues; Tumor Cell Biology; Tumor Promotion; Wasting Syndrome; Work; cancer cachexia; cell type; chemotherapy; experimental study; fat wasting; host neoplasm interaction; improved; innovation; malignant muscle neoplasm; mortality; mouse model; neoplastic cell; pancreatic cancer model; pancreatic neoplasm; prevent; public health relevance; response; skeletal muscle wasting; small molecule; therapeutic development; treatment response; tumor; tumor growth; tumor microenvironment; tumor progression; wasting

ABSTRACT Skeletal muscle wasting affects up to 80% of patients with advanced cancer and directly impacts surgical prognosis, chemotherapeutic response, morbidity, mortality, and quality of life. While considerable effort has gone into understanding how tumors (and the host response to tumors) contribute to the etiology of cancer cachexia, relatively little is known about how the cachectic state in turn influences tumor dynamics. Our long- term goal is to develop a better understanding of reciprocal tumor-host interactions to approach therapeutic development more holistically in cancer patients. We present preliminary data highlighting the role of muscle wasting with respect to tumor progression. First, we show that mice genetically engineered to resist muscle wasting exhibit enhanced survival and slower tumor growth compared to matched control mice subjected to the same tumor transplantation protocol. Second, preliminary analyses of tumors isolated from these mice point to significant differences in cell type composition and gene expression as a function of muscle wasting. Third, we observe a divergent/unique secretome associated with ongoing myofiber atrophy. This proposal builds on these exciting findings and will address the central hypothesis that skeletal muscle wasting actively promotes tumor progression. In this proposal we will 1) detail tumor progression in the presence/absence of muscle wasting and determine if wasting prevention and intervention is sufficient to augment tumor growth, and 2) interrogate the skeletal muscle secretome to better understand the fate, composition, and function of catabolic muscle breakdown products. Together, we anticipate this work being a significant and innovative step towards better understanding the dynamic and complex relationship between tumors and host tissues, such as skeletal muscle.

摘要 骨骼肌萎缩影响高达80%的晚期癌症患者，并直接影响手术 预后、化疗反应、发病率、死亡率和生活质量。虽然作出了相当大的努力， 深入了解肿瘤（以及宿主对肿瘤的反应）如何导致癌症的病因 对于恶病质，关于恶病质状态如何反过来影响肿瘤动力学的了解相对较少。我们长久以来- 长期目标是更好地理解肿瘤-宿主相互作用，以达到治疗目的。 在癌症患者中更全面地发展。我们目前的初步数据强调肌肉的作用， 在肿瘤进展方面的浪费。首先，我们展示了基因工程小鼠抵抗肌肉 与接受过以下治疗的匹配对照小鼠相比，消瘦表现出增强的存活率和较慢的肿瘤生长。 相同的肿瘤移植方案其次，对从这些小鼠中分离出的肿瘤的初步分析表明， 细胞类型组成和基因表达的显著差异作为肌肉萎缩的函数。三是 观察到与进行性肌纤维萎缩相关的发散/独特分泌体。这项建议建立在这些 令人兴奋的发现，并将解决核心假设，骨骼肌消耗积极促进肿瘤 进展在本提案中，我们将1）详细描述存在/不存在肌肉萎缩时的肿瘤进展， 确定消耗预防和干预是否足以增加肿瘤生长，以及2）询问 骨骼肌分泌组，以更好地了解分解代谢肌肉的命运，组成和功能 分解产物。我们共同期待这项工作是朝着更好地 了解肿瘤与宿主组织（如骨骼肌）之间的动态和复杂关系。