Journal
CELL REPORTS
Volume 36, Issue 7, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2021.109553
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Funding
- Chinese National Natural Science Foundation [91957118, 31800999, 31971079]
- Fundamental Research Funds for the Central Universities
- NIH [P01CA120964, R01DK121409, R01GM067761]
- American Diabetes Association [1-16-PDF-108]
- Harvard Blavatnik Accelerator Fund
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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.
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.
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