The Shh receptor Boc promotes progression of early medulloblastoma to advanced tumors

Frédéric Mille, Lukas Tamayo-Orrego, Martin Lévesque, Marc Remke, Andrey Korshunov, Julie Cardin, Nicolas Bouchard, Luisa Izzi, Marcel Kool, Paul A. Northcott, Michael D. Taylor, Stefan M. Pfister, Frédéric Charron

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)

Abstract

During cerebellar development, Sonic hedgehog (Shh) signaling drives the proliferation of granule cell precursors (GCPs). Aberrant activation of Shh signaling causes overproliferation of GCPs, leading to medulloblastoma. Although the Shh-binding protein Boc associates with the Shh receptor Ptch1 to mediate Shh signaling, whether Boc plays a role in medulloblastoma is unknown. Here, we show that BOC is upregulated in medulloblastomas and induces GCP proliferation. Conversely, Boc inactivation reduces proliferation and progression of early medulloblastomas to advanced tumors. Mechanistically, we find that Boc, through elevated Shh signaling, promotes high levels of DNA damage, an effect mediated by CyclinD1. High DNA damage in the presence of Boc increases the incidence of Ptch1 loss of heterozygosity, an important event in the progression from early to advanced medulloblastoma. Together, our results indicate that DNA damage promoted by Boc leads to the demise of its own coreceptor, Ptch1, and consequently medulloblastoma progression.

Original languageEnglish
Pages (from-to)34-47
Number of pages14
JournalDevelopmental Cell
Volume31
Issue number1
DOIs
Publication statusPublished - 13 Oct 2014
Externally publishedYes

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