Transcriptional analysis of cancer cachexia: conserved and unique features across preclinical models and biological sex

Studies suggest heterogeneity in cancer cachexia (CC) among models and biological sexes, yet examinations comparing models and sexes are scarce. We compared the transcriptional landscape of skeletal muscle across murine CC models and biological sexes during early and late CC. Global gene expression analyses were performed on gastrocnemius [Lewis lung carcinoma (LLC)], quadriceps (KPC-pancreatic), and tibialis anterior [Colon-26 (C26)-colorectal and Apc^Min/+] muscles across biological sexes. Differentially expressed genes (DEGs) were identified using an adj-P value of <0.05, followed by pathway and computational cistrome analyses. Integrating all controls, early and late stages of all models and sexes revealed up to 68% of DEGs and pathways were enriched at early and late CC, indicating a conserved transcriptional profile during CC development. Comparing DEGs and pathways within sexes and across models, in early CC, the transcriptional response was highly heterogeneous. At late stage, 11.5% of upregulated and 10% of downregulated genes were shared between models in males, whereas 18.9% of upregulated and 7% of downregulated DEGs were shared in females. Shared DEGs were enriched in proteasome and mitophagy/autophagy pathways (upregulated), and downregulation of energy metabolism pathways in males only. Between sexes, though the proportion of shared DEGs was low (<16%), similar pathway enrichment was observed, including proteasome and mitophagy at late-stage CC. In early CC, oncostatin M receptor (Osmr) upregulation was the only commonality across all models and sexes, whereas CLOCK and ARNTL/BMAL1 were predicted transcriptional factors associated with dysregulations in all three male models. This study highlights sex and model differences in CC progression and suggests conserved transcriptional changes as potential therapeutic targets.NEW & NOTEWORTHY This study is among the first to integrate and compare the skeletal muscle transcriptional landscape across multiple preclinical models and biological sexes. We highlight that 1) early CC transcriptional changes are two-thirds conserved at late stages, 2) DEGs are largely model and sex specific, and 3) transcriptional factors including CLOCK and ARNTL/BMAL1, which influence early CC gene expression, might represent a global therapeutic target with a chance of efficacy across various cancer types.