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Effect of CALCOCO2 depletion in HDMB03 Group 3 medulloblastoma cells

ABSTRACT: Medulloblastoma (MB) is the most common malignant paediatric brain tumour, with Group 3 disease representing the most aggressive and therapy-refractory subtype. Despite intensive craniospinal radiotherapy, outcomes remain poor and the molecular basis of radioresistance is unclear. Here we identify CALCOCO2 as a key determinant of Group 3 MB aggressiveness and radiotherapy resistance. CALCOCO2 is markedly upregulated in Group 3 tumours, where high expression correlates with adverse clinical outcome. We show that CALCOCO2 is transcriptionally regulated by the developmental factor OTX2, defining a previously unrecognised axis that sustains a progenitor-like, transformation-permissive state. Functionally, nuclear CALCOCO2 promotes efficient repair of radiation-induced DNA double-strand breaks by engaging POLθ-dependent alternative end joining. Disruption of the CALCOCO2–POLθ pathway impairs DNA repair, sensitizes tumour cells to radiotherapy and suppresses tumour growth in vitro and in vivo. These findings uncover a developmentally wired DNA repair dependency in Group 3 MB and highlight POLθ inhibition as a rational strategy to overcome therapeutic resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE324649 | GEO | 2026/09/01

REPOSITORIES: GEO

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Effect of CALCOCO2 depletion in HDMB03 Group 3 medulloblastoma cells

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