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Restore the brake on tumor progression
Renata E Gordon1, Li Zhang2, Zeng-Jie Yang3
1Cancer Biology Program, Fox Chase Cancer Center, Temple University Health System, Philadelphia, PA 19111, USA.
Abstract:
Sonic hedgehog (Shh) signaling plays a key role in regulation of normal development. The negative feedback mechanism mediated by the transcriptional factor, Gli3, acts to finely tune Shh signaling, providing tight control of normal developmental processes. Hyperactivation of Shh signaling often leads to many human malignancies, including basal cell carcinoma and medulloblastoma (MB). However, how tumor cells sustain the aberrant activation of Shh signaling is still not completely understood. We recently revealed that during MB formation, tumor cells express Nestin, a type VI intermediate filament protein, which maintains uncontrolled Shh signaling by abolishing negative feedback by Gli3. Therefore, Nestin expression is a necessary step for MB formation. These findings highlight the novel function of Nestin in regulating Shh signaling, as well as the important role of a disrupted negative feedback mechanism in MB tumorigenesis. Further, restoration of the intrinsic negative feedback by repressing Nestin expression represents a promising approach to treat MB as well as other Shh signaling associated malignancies.
Insights
Nestin protein fuels medulloblastoma growth by disrupting Sonic hedgehog (Shh) signaling negative feedback. Repressing Nestin offers a potential therapeutic strategy for Shh-associated cancers.
Area of Science:
- Developmental Biology
- Cancer Biology
- Molecular Oncology
Background:
- Sonic hedgehog (Shh) signaling is crucial for normal development but its hyperactivation drives malignancies like medulloblastoma (MB).
- A negative feedback loop involving Gli3 normally regulates Shh signaling, but its disruption in cancer remains incompletely understood.
Purpose of the Study:
- To elucidate the mechanism by which tumor cells sustain aberrant Shh signaling in medulloblastoma.
- To identify novel therapeutic targets for Shh-associated cancers.
Main Methods:
- Investigated the role of Nestin in medulloblastoma formation.
- Analyzed the interaction between Nestin, Gli3, and Shh signaling pathways.
Main Results:
- Tumor cells in medulloblastoma express Nestin, a protein that abolishes Gli3-mediated negative feedback on Shh signaling.
- Nestin expression is essential for medulloblastoma development by ensuring sustained Shh pathway activation.
- Disruption of the Gli3-mediated negative feedback loop is a key event in MB tumorigenesis.
Conclusions:
- Nestin plays a critical role in medulloblastoma pathogenesis by overriding normal Shh signaling regulation.
- Targeting Nestin to restore negative feedback represents a promising therapeutic avenue for medulloblastoma and other Shh-driven cancers.