Spatiotemporal Multi-Omic Mapping Reveals Liver-Muscle Metabolic Crosstalk in Cancer Cachexia.

Abstract

Tumor and host interaction contributes to cancer cachexia, a systemic wasting syndrome characterized by tissue loss (adipose and skeletal muscle), anorexia, fatigue, and metabolic reprogramming. Nevertheless, the spatio-temporal molecular dynamics of multiple tissues during cancer cachexia development remain elusive. Here, we present a comprehensive overview of the biological alterations and metabolic reprogramming of cancer cachexia across two species, 25 organs, and 3230 samples, by integrating transcriptomic, proteomic, and metabolomic profiles spanning different cachectic stages and sexual dimorphism. Using this cancer cachexia atlas (CCAtlas), we identified dysregulated tissues of cancer cachexia, including skeletal muscle, liver, and blood. We revealed coordinated metabolic reprogramming across tissues, including dysregulated amino acid metabolism and one-carbon metabolism. Temporal profiling illustrated dynamic molecular signatures during cancer cachexia progression. The exacerbated inflammatory status in males potentially contributed to a more severe whole-body wasting phenotype. The liver-muscle crosstalk potentiated skeletal muscle atrophy through creatine deficiency via hepatic Gamt downregulation in the LLC model. Creatine supplementation and hepatic Gamt overexpression in the LLC model attenuated skeletal muscle wasting. Together, CCAtlas provides fundamental and systemic insights into multi-omic molecular dynamics and metabolic rewiring of cancer cachexia from the perspective of tumor and/or inter-organ crosstalk across species.