Coordination of tumor growth and host wasting by tumor-derived Upd3

yki-induced gut tumors in Drosophila are associated with host wasting, including muscle dysfunction, lipid loss, and hyperglycemia, a condition reminiscent of human cancer cachexia. We previously used this model to identify tumor-derived ligands that contribute to host wasting. To identify additional molecular networks involved in host-tumor interactions, we develop PathON, a web-based tool analyzing the major signaling pathways in Drosophila, and uncover the Upd3/Jak/Stat axis as an important modulator. We find that ykigut tumors secrete Upd3 to promote self-overproliferation and enhance Jak/Stat signaling in host organs to cause wasting, including muscle dysfunction, lipid loss, and hyperglycemia. We further reveal that Upd3/Jak/Stat signaling in the host organs directly triggers the expression of ImpL2, an antagonistic binding protein for insulin-like peptides, to impair insulin signaling and energy balance. Altogether, our results demonstrate that yki-gut tumors produce a Jak/Stat pathway ligand, Upd3, that regulates both self-growth and host wasting.

Automated summary

The study using Drosophila model found that yki-induced gut tumors can cause host muscle dysfunction, lipid loss, and hyperglycemia, reminiscent of human cancer cachexia. By analyzing major signaling pathways and identifying the key role of the Upd3/Jak/Stat axis, the research revealed that yki-gut tumors secrete Upd3 to promote self-overproliferation and affect signaling in host organs, leading to wasting symptoms.