YAP disrupts bile acid homeostasis to drive cancer-associated cachexia [Crispant_RNAseq]
Cancer-associated cachexia is a severe metabolic syndrome marked by dramatic loss of adipose and muscle mass. Although preclinical models have advanced our understanding of cachexia, there are still no approved therapies due to the limited insights into the mechanisms underlying tissue wasting. Here, we utilise a YAP-driven model of liver cancer in zebrafish, which rapidly develops cachexia, to uncover an evolutionarily conserved role for bile acid disruption in the onset of cachexia. Spatial transcriptomic analysis revealed that YAP induces a bi-lineage cholangiocarcinoma phenotype, which was associated with bile acid dysregulation. Mechanistically, we establish that both bile acid synthesis (via CYP7A1) and signalling through the bile acid receptor TGR5 are essential for cachexia induction. Notably, we find that the promotion of bile acid excretion with odevixibat ameliorates cachexia. Together, our findings reveal an evolutionarily conserved mechanism by which YAP promotes cachexia and suggest a potential therapeutic strategy to treat the syndrome Overall design: Bulk RNA sequencing of whole zebrafish larvae at 21 days post-fertilisation (dpf), including wild-type (WT) controls and cachectic tumour-burdened p53 knockout zebrafish with constitutive hepatic YAP overexpression (PY). Samples underwent CRISPR/Cas9-mediated knockouts targeting the melanin transporter SLC45a2 (used as a pigmentation marker), either alone, (SLC45a2-KO), or in combination with the bile acid-responsive metabolic receptor TGR5 (TGR5-KO) or the classical bile acid synthesis enzyme CYP7a1 (CYP7a1-KO).