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