Project description:Many patients with advanced cancers develop cachexia. Despite the high prevalence and catastrophic impact on quality of life and survival, the critical pathobiological mediators responsible for the cancer cachexia development remain poorly defined. Here, we show that a distinct subset of neutrophil-like monocytes, which we term cachexia-inducible monocytes (CiMs), emerges in advanced cancer pathogenesis and promotes skeletal muscle loss. Unbiased transcriptome analysis revealed that IL36G-producing CD38+ CiMs are induced during cachexia progression in the pathogenesis of chronic monocytic blood cancer characterized by persistent monocytosis and cachexia. The emergence of CiMs and activation of CiM-related gene signature in inflammatory monocytes were confirmed in multiple mouse models and patients with advanced solid cancers. Notably, genetic inhibition of IL36G/IL1RL2 signaling attenuated skeletal muscle loss and rescued cachexia phenotypes derived by both blood and solid cancers in mice. These data highlight the critical role for a subset of neutrophil-like monocyte induced in cancer pathogenesis.
Project description:Many patients with advanced cancers develop cachexia. Despite the high prevalence and catastrophic impact on quality of life and survival, the critical pathobiological mediators responsible for the cancer cachexia development remain poorly defined. Here, we show that a distinct subset of neutrophil-like monocytes, which we term cachexia-inducible monocytes (CiMs), emerges in advanced cancer pathogenesis and promotes skeletal muscle loss. Unbiased transcriptome analysis revealed that IL36G-producing CD38+ CiMs are induced during cachexia progression in the pathogenesis of chronic monocytic blood cancer characterized by persistent monocytosis and cachexia. The emergence of CiMs and activation of CiM-related gene signature in inflammatory monocytes were confirmed in multiple mouse models and patients with advanced solid cancers. Notably, genetic inhibition of IL36G/IL1RL2 signaling attenuated skeletal muscle loss and rescued cachexia phenotypes derived by both blood and solid cancers in mice. These data highlight the critical role for a subset of neutrophil-like monocyte induced in cancer pathogenesis.
