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Updated: Jul 15, 2026
Induction and Diagnosis of Tumors in Drosophila Imaginal Disc Epithelia
Published on: July 25, 2017
Loss of suppressor-of-fused function promotes tumorigenesis
1Department of Genetics and Tumor Cell Biology, St Jude Children's Research Hospital, Memphis, TN 38405, USA.
Abstract:
The Sonic Hedgehog (SHH) signaling pathway is indispensable for development, and functions to activate a transcriptional program modulated by the GLI transcription factors. Here, we report that loss of a regulator of the SHH pathway, Suppressor of Fused (Sufu), resulted in early embryonic lethality in the mouse similar to inactivation of another SHH regulator, Patched1 (Ptch1). In contrast to Ptch1+/- mice, Sufu+/- mice were not tumor prone. However, in conjunction with p53 loss, Sufu+/- animals developed tumors including medulloblastoma and rhabdomyosarcoma. Tumors present in Sufu+/-p53-/- animals resulted from Sufu loss of heterozygosity. Sufu+/-p53-/- medulloblastomas also expressed a signature gene expression profile typical of aberrant SHH signaling, including upregulation of N-myc, Sfrp1, Ptch2 and cyclin D1. Finally, the Smoothened inhibitor, hedgehog antagonist, did not block growth of tumors arising from Sufu inactivation. These data demonstrate that Sufu is essential for development and functions as a tumor suppressor.
Insights
Suppressor of Fused (Sufu) is crucial for embryonic development. Loss of Sufu, especially with p53 loss, promotes tumors like medulloblastoma, indicating its role as a tumor suppressor.
Area of Science:
- Developmental Biology
- Cancer Biology
- Molecular Oncology
Background:
- The Sonic Hedgehog (SHH) signaling pathway regulates critical developmental processes.
- Transcription factors GLI modulate SHH pathway activity.
- Suppressor of Fused (Sufu) and Patched1 (Ptch1) are key regulators of the SHH pathway.
Purpose of the Study:
- To investigate the role of Suppressor of Fused (Sufu) in embryonic development and tumor suppression.
- To determine the impact of Sufu loss of heterozygosity in conjunction with p53 deficiency on tumor formation.
Main Methods:
- Generation and analysis of Sufu+/- and Sufu+/-p53-/- mouse models.
- Tumorigenesis assessment, including medulloblastoma and rhabdomyosarcoma.
- Gene expression profiling of Sufu+/-p53-/- medulloblastomas.
- Evaluation of Smoothened inhibitor efficacy on Sufu-inactivated tumors.
Main Results:
- Sufu loss caused early embryonic lethality, similar to Ptch1 inactivation.
- Sufu+/- mice were not inherently tumor-prone, unlike Ptch1+/- mice.
- Sufu+/-p53-/- mice developed medulloblastoma and rhabdomyosarcoma due to Sufu loss of heterozygosity.
- Tumors exhibited aberrant SHH signaling gene expression, including N-myc and cyclin D1 upregulation.
- Hedgehog antagonist treatment did not inhibit tumor growth from Sufu inactivation.
Conclusions:
- Sufu is essential for normal embryonic development.
- Sufu acts as a tumor suppressor, with its loss contributing to specific cancers.
- SHH pathway dysregulation in Sufu-deficient tumors is independent of Smoothened activity.
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