Journal
NATURE CANCER
Volume 1, Issue 8, Pages 840-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s43018-020-0094-7
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Funding
- Caldas (Colciencias)
- Djavad Mowafaghian Foundation
- EMBO Long-Term Fellowship [ALTF-739-2019]
- Natural Sciences and Engineering Research Council of Canada
- Canadian Institutes of Health Research [FDN334023]
- Fonds de Recherche du Quebec<bold>-</bold>Sante
- Canada Foundation for Innovation [33768]
- Canadian Cancer Society Research Institute [702310]
- Medical Research Council [MC_UU_00007/5]
- European Union's Horizon 2020 Research and Innovation Programme ERC Advanced Grant [788093]
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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. Charron and colleagues describe a form of Sonic hedgehog-induced replicative stress through Cdc7-dependent origin firing that contributes to medulloblastoma tumorigenesis.
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