Multi-organ transcriptome profiling in an isogenic cachexia-inducing xenograft model to dissect host responses across...

Cancer cachexia is a debilitating systemic syndrome that affects a substantial proportion of patients with advanced malignancy and is associated with impaired treatment tolerance, reduced quality of life, and increased mortality. While skeletal muscle wasting is a defining clinical feature, cachexia involves coordinated dysfunction across multiple organs, yet it remains unclear whether cachexia imposes a unified, body-wide transcriptional program or primarily induces organ-specific responses. Here, we leveraged an isogenic xenograft model derived from human duodenal neuroendocrine carcinoma in which the cachexia-inducing subline AkuNEC was established through in vivo serial passaging from the parental, largely non-cachexia-inducing line TCC-NECT-2. We performed bulk RNA sequencing of skeletal muscle, liver, kidney, and heart from cachectic AkuNEC-bearing mice, non-cachectic TCC-NECT-2-bearing mice, and uninoculated controls. Differential expression analyses identified organ-dependent sets of transcripts associated with cachexia. However, unsupervised analyses of global expression patterns consistently showed that tissue identity dominated transcriptome structure and samples did not segregate by cachexia status. In addition, comparisons of tumor-bearing vs uninoculated controls revealed broadly similar transcriptional shifts for AkuNEC and TCC-NECT-2 within each organ. Together, these data indicate that cachexia-associated transcriptional changes are present but remain modest relative to dominant tissue-specific programs at the whole-transcriptome level. The AkuNEC/TCC-NECT-2 system provides a controlled platform for future studies incorporating cell-type-resolved, spatial, and multi-omic approaches to delineate the mechanisms linking tumor evolution to multi-organ remodeling in cancer cachexia.