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.
Project description:Epigenetic changes including DNA methylation caused by environmental exposures may contribute to the heterogeneous inflammatory response in asthma. Here we investigate alterations in DNA methylation of purified blood monocytes that are associated with inflammatory phenotypes of asthma.
Project description:Cancer cachexia is a multifactorial condition characterized by skeletal muscle loss that impairs longevity and quality of life of the vast majority of cancer patients. However, the ability to develop therapeutic strategies to counter cachexia is impeded by the limited understanding of the underlying mechanisms of cachexia in human cancer patients. The purpose of this study was therefore to characterize the proteomic signature of skeletal muscle obtained from cachectic pancreatic ductal adenocarcinoma (PDAC) patients, who exhibit one of the highest rates of cachexia. Muscle biopsies (rectus abdominis) were obtained from PDAC patients (n=8; 70±10yr; BMI: 26.8±5.9kg・m-2) undergoing tumor resection surgery as well as age and sex-matched non-cancer controls (n=6; 66±9yr; BMI: 30.8±5.2kg・m-2). PDAC patients were cachectic (6 month body weight loss > 5%; mean: 15.7±7.9%) and did not undergo neoadjuvant therapy.