An Oatp transporter-mediated steroid sink promotes tumor-induced cachexia in Drosophila

Abstract

Cancer cachexia is a multifactorial syndrome associated with many types of tumors and characterized by a combination of anorexia, loss of body weight, catabolic alterations and systemic inflammation. We developed a tumor model in Drosophila larvae causing a cachexia-like syndrome, and used it to evaluate the role of steroid hormone imbalance in cachectic alterations. Cachectic larvae show reduced levels of the circulating steroid ecdysone. Artificially importing ecdysone in the tumor using the Oatp74D importer aggravates cachexia, while feeding animals with ecdysone rescues cachectic defects. This suggests that a steroid sink induced by the tumor promotes catabolic alterations in healthy tissues. We find that Oatp33Eb, another member of this family of transporters, is specifically induced in tumors promoting cachexia. Blocking Oatp33Eb in cachectic tumors restores circulating ecdysone and reverses cachectic alterations. Oatp transporters are induced in several types of hormone-dependent tumors, suggesting that a similar sink effect could modify hormonal balance in cachectic cancer patients. Highlights- We used the Drosophila larva as a model to study hormonal imbalance in tumor-induced cachexia. - Steroid (ecdysone) levels are reduced in cachectic tumor-bearing larvae. - Steroid import by the tumor reduces circulating hormone levels and induces cachexia. - The Oatp33Eb transporter is specifically upregulated in cachectic tumors and its inhibition rescues both circulating steroid levels and metabolic/tissue homeostasis. - Specific Oatp genes are found upregulated in human tumors with high prevalence of cachexia.