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.

抽象的 骨骼肌浪费会影响多达80％的晚期癌症患者，并直接影响手术 预后，化学治疗反应，发病率，死亡率和生活质量。虽然很大的努力 了解肿瘤（以及宿主对肿瘤的反应）如何促进癌症的病因 缓存状态如何影响肿瘤动力学如何，恶病质，相对较少了解。我们的长期 术语目标是更好地理解对相互肿瘤 - 宿主相互作用以进行治疗 癌症患者的整体发展更加全面。我们提出了强调肌肉作用的初步数据 浪费肿瘤进展。首先，我们表明小鼠在基因上进行了抗拒肌肉 与受到匹配的对照小鼠相比 相同的肿瘤移植方案。其次，对从这些小鼠分离的肿瘤的初步分析指向 细胞类型组成和基因表达的显着差异是肌肉浪费的函数。第三，我们 观察与持续的肌纤维萎缩有关的不同/独特的分泌组。该提议以这些为基础 令人兴奋的发现，并将解决骨骼肌浪费积极促进肿瘤的中心假设 进展。在此提案中，我们将1）详细说明在存在/不存在肌肉浪费和 确定预防浪费和干预是否足以增加肿瘤的生长，2）询问 骨骼肌肉分泌型，以更好地了解分解代谢肌肉的命运，成分和功能 故障产品。我们共同预计这项工作是迈向更好的重要而创新的一步 了解肿瘤与宿主组织之间的动态和复杂关系，例如骨骼肌。