Aberrations in Notch-Hedgehog signalling reveal cancer stem cells harbouring conserved oncogenic properties associated with hypoxia and immunoevasion
A partir de l'analyse du nombre de copies de gènes de la voie de signalisation Notch-Hedgehog dans les cellules souches cancéreuses de 21 types de cancers, cette étude met en évidence une association entre un panel de 13 gènes fréquemment amplifiés dans 5 types de cancers et le caractère hypoxique de la tumeur, l'échappement des cellules cancéreuses au système immunitaire ainsi que le risque de décès
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.
British Journal of Cancer , résumé, 2019