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Tumors overcome the action of the wasting factor ImpL2 by locally elevating Wnt/Wingless
Jiae Lee1, Katelyn G-L Ng1, Kenneth M Dombek1
1Department of Biochemistry, School of Medicine, University of Washington, Seattle, WA 98195.
Abstract:
Tumors often secrete wasting factors associated with atrophy and the degeneration of host tissues. If tumors were to be affected by the wasting factors, mechanisms allowing tumors to evade the adverse effects of the wasting factors must exist, and impairing such mechanisms may attenuate tumors. We use Drosophila midgut tumor models to show that tumors up-regulate Wingless (Wg) to oppose the growth-impeding effects caused by the wasting factor, ImpL2 (insulin-like growth factor binding protein [IGFBP]-related protein). Growth of Yorkie (Yki)-induced tumors is dependent on Wg while either elimination of ImpL2 or elevation of insulin/insulin-like growth factor signaling in tumors revokes this dependency. Notably, Wg augmentation could be a general mechanism for supporting the growth of tumors with elevated ImpL2 and exploited to attenuate muscle degeneration during wasting. Our study elucidates the mechanism by which tumors negate the action of ImpL2 to uphold their growth during cachexia-like wasting and implies that targeting the Wnt/Wg pathway might be an efficient treatment strategy for cancers with elevated IGFBPs.
Insights
Tumors evade wasting factors by increasing Wingless (Wg) signaling to counteract ImpL2
Area of Science:
- Molecular Biology
- Cancer Research
- Developmental Biology
Background:
- Tumors can secrete wasting factors that cause host tissue atrophy.
- Tumors must possess mechanisms to resist these wasting factors to survive.
- Understanding tumor evasion strategies is crucial for developing cancer therapies.
Purpose of the Study:
- To investigate the mechanisms by which tumors evade the effects of wasting factors.
- To explore the role of Wingless (Wg) and ImpL2 in tumor growth during wasting conditions.
- To identify potential therapeutic targets for cancers experiencing cachexia-like wasting.
Main Methods:
- Utilized *Drosophila* midgut tumor models.
- Analyzed the up-regulation of Wingless (Wg) in response to ImpL2.
- Investigated the dependency of Yorkie (Yki)-induced tumor growth on Wg signaling.
- Examined the effects of *ImpL2* elimination and insulin/IGF signaling modulation.
Main Results:
- Tumors up-regulate Wingless (Wg) to oppose the growth-inhibiting effects of ImpL2.
- Yorkie (Yki)-induced tumor growth is dependent on Wg signaling.
- Eliminating ImpL2 or increasing insulin/IGF signaling in tumors reduces Wg dependency.
- Wg augmentation supports tumor growth in the presence of elevated ImpL2.
Conclusions:
- Tumors employ Wg up-regulation to counteract ImpL2-mediated wasting and maintain growth.
- Targeting the Wnt/Wg pathway may be a viable treatment strategy for cancers with elevated IGFBPs.
- This mechanism highlights a potential approach to attenuate muscle degeneration during wasting conditions.
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