Chang, WH;
Lai, AG;
(2019)
Aberrations in Notch-Hedgehog signalling reveal cancer stem cells harbouring conserved oncogenic properties associated with hypoxia and immunoevasion.
British Journal of Cancer
, 121
pp. 666-678.
10.1038/s41416-019-0572-9.
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Abstract
BACKGROUND: 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. // METHODS: 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. // RESULTS: 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. // CONCLUSION: 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.
| Type: | Article |
|---|---|
| Title: | Aberrations in Notch-Hedgehog signalling reveal cancer stem cells harbouring conserved oncogenic properties associated with hypoxia and immunoevasion |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41416-019-0572-9 |
| Publisher version: | https://doi.org/10.1038/s41416-019-0572-9 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Cancer microenvironment, Cancer screening, Cancer stem cells |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Health Informatics |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10082121 |
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