The developmental stage of the medulloblastoma cell-of-origin restricts Sonic hedgehog pathway usage and drug sensitivity.
Cerebellar development
Cerebellar granule neuron progenitors
Medulloblastoma
Primary cilia
Sonic hedgehog signaling
Tumor cell-of-origin
Journal
Journal of cell science
ISSN: 1477-9137
Titre abrégé: J Cell Sci
Pays: England
ID NLM: 0052457
Informations de publication
Date de publication:
01 06 2022
01 06 2022
Historique:
received:
05
03
2021
accepted:
03
05
2022
pubmed:
11
5
2022
medline:
10
6
2022
entrez:
10
5
2022
Statut:
ppublish
Résumé
Sonic hedgehog (SHH) medulloblastoma originates from the cerebellar granule neuron progenitor (CGNP) lineage, which depends on Hedgehog signaling for its perinatal expansion. Whereas SHH tumors exhibit overall deregulation of this pathway, they also show patient age-specific aberrations. To investigate whether the developmental stage of the CGNP can account for these age-specific lesions, we analyzed developing murine CGNP transcriptomes and observed highly dynamic gene expression as a function of age. Cross-species comparison with human SHH medulloblastoma showed partial maintenance of these expression patterns, and highlighted low primary cilium expression as hallmark of infant medulloblastoma and early embryonic CGNPs. This coincided with reduced responsiveness to upstream SHH pathway component Smoothened, whereas sensitivity to downstream components SUFU and GLI family proteins was retained. Together, these findings can explain the preference for SUFU mutations in infant medulloblastoma and suggest that drugs targeting the downstream SHH pathway will be most appropriate for infant patients.
Identifiants
pubmed: 35535520
pii: 275628
doi: 10.1242/jcs.258608
pmc: PMC9234672
pii:
doi:
Substances chimiques
Hedgehog Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : UMCG Kanker Researchfonds (KRF)
Organisme : Stichting De Cock-Hadders
Organisme : Indonesian Endowment Fund for Education (LPDP)
ID : 20151022024475
Organisme : Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior
Organisme : University of Groningen and European Union
Organisme : Netherlands Organisation for Scientific Research (NWO)
Organisme : Stichting vrienden Beatrix Kinderziekenshuis
Organisme : KWF Kankerbestrijding
ID : RUG 2014-6903
Organisme : UMCG Kanker Researchfonds
Organisme : Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Organisme : University of Groningen
Organisme : European Union
Organisme : Netherlands Organisation for Scientific Research
Organisme : Stichting Vrienden Beatrix Kinderziekenhuis
Organisme : Universitair Medisch Centrum Groningen
Informations de copyright
© 2022. Published by The Company of Biologists Ltd.
Déclaration de conflit d'intérêts
Competing interests The authors declare no competing or financial interests.
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