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Br J Cancer. 2019 Oct;121(8):666-678. doi: 10.1038/s41416-019-0572-9. Epub 2019 Sep 16.

Aberrations in Notch-Hedgehog signalling reveal cancer stem cells harbouring conserved oncogenic properties associated with hypoxia and immunoevasion.

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Institute of Health Informatics, University College London, 222 Euston Road, London, NW1 2DA, UK.
Institute of Health Informatics, University College London, 222 Euston Road, London, NW1 2DA, UK.



Cancer stem cells (CSCs) have innate abilities to resist even the harshest of therapies. To eradicate CSCs, parallels can be drawn from signalling modules that orchestrate pluripotency. Notch-Hedgehog hyperactivation are seen in CSCs, yet, not much is known about their conserved roles in tumour progression across cancers.


Employing a comparative approach involving 21 cancers, we uncovered clinically-relevant, pan-cancer drivers of Notch and Hedgehog. GISTIC datasets were used to evaluate copy number alterations. Receiver operating characteristic and Cox regression were employed for survival analyses.


We identified a Notch-Hedgehog signature of 13 genes exhibiting high frequencies of somatic amplifications leading to transcript overexpression. The signature successfully predicted patients at risk of death in five cancers (n = 2278): glioma (P < 0.0001), clear cell renal cell (P = 0.0022), papillary renal cell (P = 0.00099), liver (P = 0.014) and stomach (P = 0.011). The signature was independent of other clinicopathological parameters and offered an additional resolution to stratify similarly-staged tumours. High-risk patients exhibited features of stemness and had more hypoxic tumours, suggesting that hypoxia may influence CSC behaviour. Notch-Hedgehog+ CSCs had an immune privileged phenotype associated with increased regulatory T cell function.


This study will set the stage for exploring adjuvant therapy targeting the Notch-Hedgehog axis to help optimise therapeutic regimes leading to successful CSC elimination.


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