Cachexia is a systemic condition that accompanies many diseases, including cancer, and involves muscle wasting, weight loss, and metabolic changes that can cause death or accelerate death due to the underlying disease. Studies from Kwon et al. and Figueroa-Clarevega and Bilder investigated how populations of hyperproliferating cells induce a condition similar to cachexia in the fruit fly Drosophila melanogaster. Using inducible expression of an activated form of the transcriptional coactivator Yorkie (ykiact) specifically in intestinal stem cells of the midgut, Kwon et al. found that the presence of hyperproliferating cells caused degeneration of the ovaries and body fat, impaired muscle function, and increased the volume of hemolymph in the abdomen, causing bloating. The muscles of ykiact flies exhibited morphological and transcriptomic changes indicative of mitochondrial dysfunction and reduced metabolic processes, including glycolysis. The ovaries likewise showed reduced expression of genes involved in glycolysis. Changes in the abundance of metabolites in the hemolymph and in the abundance of a marker of insulin signaling were consistent with systemic metabolic dysfunction, hyperglycemia, and reduced insulin signaling. Although glycolysis was reduced in other tissues, the hyperproliferating cells themselves exhibited increased glycolysis and insulin signaling. The secreted protein ImpL2 binds to circulating Drosophila insulin-like peptides (Dilps) to reduce insulin signaling. Hyperproliferating gut cells had increased expression of ImpL2 compared with controls, but expression of ImpL2 was not affected in ovaries or muscles. Reducing ImpL2 expression specifically in the midgut rescued the metabolic and morphological phenotypes and restored insulin signaling in ykiact flies.
In a related paper, Figueroa-Clarevega and Bilder observed the same wasting syndrome following the transplantation of tumorous larval imaginal discs into the abdomens of adult flies. Using different combinations of mutations that transformed imaginal discs into neoplastic (malignant) or hyperplastic (benign) tumors, the authors observed that only malignant tumors induced the wasting syndrome. Transcriptomic analysis revealed that malignant tumors produced more ImpL2 than benign tumors or wild-type imaginal discs. Overexpression of ImpL2 in the hindgut was sufficient to induce wasting phentoypes, and reducing ImpL2 expression in transplanted tumors with an inducible RNA interference construct partially reversed wasting phenotypes, which may indicate that other factors are involved in systemic wasting induced by malignant tumors. This study also demonstrated that morphological changes in the fat bodies of tumor-bearing animals were consistent with lipid mobilization, that tumor-bearing animals had changes in circulating metabolites consistent with hyperglycemia, and that insulin signaling was reduced in nontumor tissues. Both studies demonstrated that, like cachexia in human patients, wasting syndrome in flies was not improved by increasing caloric intake. Findings from both studies are consistent with secretion of the insulin antagonist ImpL2 inducing cachexia by changing glucose metabolism in nontumor tissues, resulting in degeneration of those tissues. Proinflammatory cytokines have been implicated in inducing cachexia in mammalian systems, but these studies in Drosophila suggest that exploration of the involvement of insulin-signaling modifiers in mammalian systems may uncover additional factors that play a role in cachexia associated with cancer and other diseases.
Y. Kwon, W. Song, I. A. Droujinine, Y. Hu, J. M. Asara, N. Perrimon, Systemic organ wasting induced by localized expression of the secreted insulin/IGF antagonist ImpL2. Dev. Cell 33, 36–46 (2015). [PubMed]
A. Figueroa-Clarevega, D. Bilder, Malignant Drosophila tumors interrupt insulin signaling to induce cachexia-like wasting. Dev. Cell 33, 47–55 (2015). [PubMed]