Sonic hedgehog accelerates DNA replication to cause replication stress promoting cancer initiation in medulloblastoma
Fiche du document
15 novembre 2021
- handle: 10670/1.lke0zt
- doi: 10.1038/s43018-020-0094-7
Sujets proches
Carcinoma Cancers Malignancy (Cancer) Malignant tumorsCiter ce document
Lukas Tamayo-Orrego et al., « Sonic hedgehog accelerates DNA replication to cause replication stress promoting cancer initiation in medulloblastoma », Papyrus : le dépôt institutionnel de l'Université de Montréal, ID : 10.1038/s43018-020-0094-7
Métriques
Partage / Export
Résumé
The mechanisms generating cancer-initiating mutations are not well understood. Sonic hedgehog (SHH) pathway activation is frequent in medulloblastoma (MB), with PTCH1 mutations being a common initiating event. Here we investigated the role of the developmental mitogen SHH in initiating carcinogenesis in the cells of origin: granule cell progenitors (GCPs). We delineate a molecular mechanism for tumor initiation in MB. Exposure of GCPs to Shh causes a distinct form of DNA replication stress, increasing both origin firing and fork velocity. Shh promotes DNA helicase loading and activation, with increased Cdc7-dependent origin firing. The S-phase duration is reduced and hyper-recombination occurs, causing copy number neutral loss of heterozygosity—a frequent event at the PTCH1/ptch1 locus. Moreover, Cdc7 inhibition to attenuate origin firing reduces recombination and preneoplastic tumor formation in mice. Therefore, tissue-specific replication stress induced by Shh promotes loss of heterozygosity, which in tumor-prone Ptch1+/− GCPs results in loss of this tumor suppressor—an early cancer-initiating event.