Cancer-cell-secreted extracellular vesicles target p53 to impair mitochondrial function in muscle

Skeletal muscle loss and weakness are associated with bad prognosis and poorer quality of life in cancer patients. Tumor-derived factors have been implicated in muscle dysregulation by inducing cachexia and apoptosis. Here, we show that extracellular vesicles secreted by breast cancer cells impair mitochondrial homeostasis and function in skeletal muscle, leading to decreased mitochondrial content and energy production and increased oxidative stress. Mechanistically, miR-122-5p in cancer-cell-secreted EVs is transferred to myocytes, where it targets the tumor suppressor TP53 to decrease the expression of TP53 target genes involved in mitochondrial regulation, including Tfam, Pgc-1α, Sco2, and 16S rRNA. Restoration of Tp53 in muscle abolishes mitochondrial myopathology in mice carrying breast tumors, and partially rescues their impaired running capacity without significantly affecting muscle mass. We conclude that extracellular vesicles from breast cancer cells mediate skeletal muscle mitochondrial dysfunction in cancer and may contribute to muscle weakness in some cancer patients.

癌症患者出现骨骼肌丢失与肌无力症状，往往与不良预后及生活质量下降密切相关。肿瘤衍生因子可通过诱导恶病质与细胞凋亡引发肌肉功能失调，这一关联已得到学界广泛证实。本研究发现，乳腺癌细胞分泌的细胞外囊泡（extracellular vesicles, 简称EVs）会破坏骨骼肌的线粒体稳态与功能，进而导致线粒体含量降低、能量生成减少，并加剧氧化应激。从机制层面来看，乳腺癌细胞分泌的EVs中含有的miR-122-5p可被转运至肌细胞内，通过靶向抑癌基因TP53，下调一系列参与线粒体调控的TP53靶基因的表达，其中包括Tfam、Pgc-1α、Sco2以及16S rRNA。在荷乳腺癌小鼠的骨骼肌中恢复Tp53表达，可完全逆转其线粒体相关肌病变，并部分改善其受损的运动能力，且不会显著改变肌肉质量。综上，乳腺癌细胞分泌的EVs可介导癌症状态下的骨骼肌线粒体功能障碍，或为部分癌症患者出现肌无力症状的潜在诱因之一。