Proteome‐Wide Dissection of Cachexia‐Inducing Evolution in a Paired Human Neuroendocrine Carcinoma Cell Line Model

Cancer cachexia is a devastating systemic syndrome, yet tumor-intrinsic programs that enable cachexia induction remain poorly defined. Here we dissect cachexia-inducing tumor evolution using a uniquely paired model derived from a rare human duodenal neuroendocrine carcinoma, in which repeated in vivo passaging converts a non-cachexia-inducing cell line (TCC-NECT-2) into a cachexia-inducing derivative (AkuNEC). AkuNEC xenografts reproducibly induced progressive body weight loss, whereas TCC-NECT-2 xenografts did not. Using data-independent acquisition (DIA) proteomics, we quantified the proteomes of the paired cell lines and their matched xenograft tumors and performed complementary comparisons (cell line-to-cell line, cell-to-tumor within each lineage, and tumor-to-tumor). Proteomic profiling revealed robust divergence between TCC-NECT-2 and AkuNEC cells in vitro, and extensive remodeling upon xenograft formation in both lineages. Importantly, cachexia-inducing tumors displayed lineage-specific in vivo remodeling and an in vivo tumor proteome enriched for epithelial-mesenchymal transition, hypoxia, and cholesterol homeostasis, whereas no significant pathway enrichment was detected among proteins decreased in AkuNEC tumors under the applied false discovery rate (FDR) threshold. These results establish cachexia as an acquired tumor phenotype shaped by in vivo selection and provide a proteome-wide resource for prioritizing tumor-intrinsic candidates for future functional studies.