Skeletal muscle stem cells reprogramming potentiates cancer cachexia

Cancer cachexia is characterized by skeletal muscle wasting and fibrosis. Elucidating how tumor cells interact with muscle stem cells (MuSCs) will be crucial for preventing the progression of cancer cachexia. Nevertheless, the underlying mechanisms by which MuSCs promote cancer cachexia remain elusive. Herein, we investigated the heterogenous states and functional reprogramming of skeletal MuSCs in cancer cachexia. We identified a subtype of MuSCs, transitional MuSCs (Tran-MuSCs), that was enriched during MuSCs differentiation in cachectic skeletal muscle tissues. Tumor cells skewed the differentiation of MuSCs towards a pro-fibrotic phenotype through hypoxia mediated lysyl oxidase (Lox) upregulation, which thereby increased fibrosis through collagen crosslinking. Mechanistically, tumor-derived factors interacted with MuSCs by activating Spp1-αVβ1 integrin-Lox axis to promote muscle fibrosis under hypoxic microenvironment. Inhibition of Lox alleviated cachectic muscle manifestations. Overall, our findings unveil that MuSCs play a critical role in promoting cachectic manifestations and inform therapeutic biomarkers for cancer cachexia.