Aberrant FGF signaling promotes granule neuron precursor expansion in SHH subgroup infantile medulloblastoma
Mutations in Sonic Hedgehog (SHH) signaling pathway genes, for example, Suppressor of Fused (SUFU), drive granule neuron precursors (GNP) to form medulloblastomas (MBSHH). However, how different molecular lesions in the Shh pathway drive transformation is frequently unclear, and SUFU mutations in th...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2025-01-01
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| Online Access: | https://elifesciences.org/articles/100767 |
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| author | Odessa R Yabut Jessica Arela Hector G Gomez Jesse Garcia Castillo Thomas Ngo Samuel J Pleasure |
| author_facet | Odessa R Yabut Jessica Arela Hector G Gomez Jesse Garcia Castillo Thomas Ngo Samuel J Pleasure |
| author_sort | Odessa R Yabut |
| collection | DOAJ |
| description | Mutations in Sonic Hedgehog (SHH) signaling pathway genes, for example, Suppressor of Fused (SUFU), drive granule neuron precursors (GNP) to form medulloblastomas (MBSHH). However, how different molecular lesions in the Shh pathway drive transformation is frequently unclear, and SUFU mutations in the cerebellum seem distinct. In this study, we show that fibroblast growth factor 5 (FGF5) signaling is integral for many infantile MBSHH cases and that FGF5 expression is uniquely upregulated in infantile MBSHH tumors. Similarly, mice lacking SUFU (Sufu-cKO) ectopically express Fgf5 specifically along the secondary fissure where GNPs harbor preneoplastic lesions and show that FGFR signaling is also ectopically activated in this region. Treatment with an FGFR antagonist rescues the severe GNP hyperplasia and restores cerebellar architecture. Thus, direct inhibition of FGF signaling may be a promising and novel therapeutic candidate for infantile MBSHH. |
| format | Article |
| id | doaj-art-a9d7f631518140c4bb177001ed9a98f0 |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj-art-a9d7f631518140c4bb177001ed9a98f02025-01-21T13:26:03ZengeLife Sciences Publications LtdeLife2050-084X2025-01-011310.7554/eLife.100767Aberrant FGF signaling promotes granule neuron precursor expansion in SHH subgroup infantile medulloblastomaOdessa R Yabut0Jessica Arela1Hector G Gomez2https://orcid.org/0000-0002-8894-0093Jesse Garcia Castillo3Thomas Ngo4Samuel J Pleasure5https://orcid.org/0000-0001-8599-1613Department of Neurology, Weill Institute for Neuroscience, University of California San Francisco, San Francisco, United StatesDepartment of Neurology, Weill Institute for Neuroscience, University of California San Francisco, San Francisco, United StatesDepartment of Neurology, Weill Institute for Neuroscience, University of California San Francisco, San Francisco, United StatesDepartment of Neurology, Weill Institute for Neuroscience, University of California San Francisco, San Francisco, United StatesDepartment of Neurology, Weill Institute for Neuroscience, University of California San Francisco, San Francisco, United StatesDepartment of Neurology, Weill Institute for Neuroscience, University of California San Francisco, San Francisco, United StatesMutations in Sonic Hedgehog (SHH) signaling pathway genes, for example, Suppressor of Fused (SUFU), drive granule neuron precursors (GNP) to form medulloblastomas (MBSHH). However, how different molecular lesions in the Shh pathway drive transformation is frequently unclear, and SUFU mutations in the cerebellum seem distinct. In this study, we show that fibroblast growth factor 5 (FGF5) signaling is integral for many infantile MBSHH cases and that FGF5 expression is uniquely upregulated in infantile MBSHH tumors. Similarly, mice lacking SUFU (Sufu-cKO) ectopically express Fgf5 specifically along the secondary fissure where GNPs harbor preneoplastic lesions and show that FGFR signaling is also ectopically activated in this region. Treatment with an FGFR antagonist rescues the severe GNP hyperplasia and restores cerebellar architecture. Thus, direct inhibition of FGF signaling may be a promising and novel therapeutic candidate for infantile MBSHH.https://elifesciences.org/articles/100767Sonic HedgehogSufumedulloblastomap53 |
| spellingShingle | Odessa R Yabut Jessica Arela Hector G Gomez Jesse Garcia Castillo Thomas Ngo Samuel J Pleasure Aberrant FGF signaling promotes granule neuron precursor expansion in SHH subgroup infantile medulloblastoma eLife Sonic Hedgehog Sufu medulloblastoma p53 |
| title | Aberrant FGF signaling promotes granule neuron precursor expansion in SHH subgroup infantile medulloblastoma |
| title_full | Aberrant FGF signaling promotes granule neuron precursor expansion in SHH subgroup infantile medulloblastoma |
| title_fullStr | Aberrant FGF signaling promotes granule neuron precursor expansion in SHH subgroup infantile medulloblastoma |
| title_full_unstemmed | Aberrant FGF signaling promotes granule neuron precursor expansion in SHH subgroup infantile medulloblastoma |
| title_short | Aberrant FGF signaling promotes granule neuron precursor expansion in SHH subgroup infantile medulloblastoma |
| title_sort | aberrant fgf signaling promotes granule neuron precursor expansion in shh subgroup infantile medulloblastoma |
| topic | Sonic Hedgehog Sufu medulloblastoma p53 |
| url | https://elifesciences.org/articles/100767 |
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