Progressive development of melanoma-induced cachexia differentially impacts organ systems in mice

Cachexia is a systemic wasting syndrome that increases cancer-associated mortality. How cachexia progressively and differentially impacts distinct tissues is largely unknown. Here, we find that the heart and skeletal muscle undergo wasting at early stages and are the tissues transcriptionally most impacted by cachexia. We also identify general and organ-specific transcriptional changes that indicate functional derangement by cachexia even in tissues that do not undergo wasting, such as the brain. Secreted factors constitute a top category of cancer-regulated genes in host tissues, and these changes include upregulation of the angiotensin-converting enzyme (ACE). ACE inhibition with the drug lisinopril improves muscle force and partially impedes cachexia-induced transcriptional changes, although wasting is not prevented, suggesting that cancer-induced host-secreted factors can regulate tissue function during cachexia. Altogether, by defining prevalent and temporal and tissue-specific responses to cachexia, this resource highlights biomarkers and possible targets for general and tissue-tailored anti-cachexia therapies. [Display omitted] •Cancer cachexia induces prevalent, as well as temporal and tissue-specific, changes•Cachexia causes dysfunction also in tissues that do not atrophy, such as the brain•Secreted factors are a top category of cancer-regulated genes in host tissues•Inhibition of the secreted factor ACE impedes cachexia-induced muscle weakness Graca et al. examine the transcriptional and cellular changes that occur during the progression of cancer cachexia in mice and identify general and organ-specific transcriptional changes that underlie the differential propensity and temporal dynamics of cancer-induced tissue wasting and dysfunction. This resource highlights biomarkers and possible targets for anti-cachexia therapies.