Journal
ONCOGENE
Volume 37, Issue 11, Pages 1417-1429Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41388-017-0039-5
Keywords
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Funding
- Institut National du Cancer [PRT-K 14061]
- Ligue Nationale contre le Cancer (Equipe labellisee)
- Association Hubert Gouin Enfance et Cancer
- Les Bagouz a Manon, les amis de Claire
- la Federation Enfants et Sante et la Societe Francaise de Lutte contre les Cancers et les Leucemies de l'Enfant et l'Adolescent
- Fondation pour la Recherche Medicale [FDT20140930966]
- Institut Curie-SIRIC (Site de Recherche Integree en Cancerologie) program
- ATIP-Avenir program
- Who am I? program
- Agence Nationale de la Recherche (Investissements d'Avenir program) [ANR-10-EQPX-03, ANR-10-INBS-09-08]
- Canceropole Ile-de-France
- SiRIC-Curie program-SiRIC [INCa-DGOS-4654]
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Activating mutations of the ALK receptor occur in a subset of neuroblastoma tumors. We previously demonstrated that Alk mutations cooperate with MYCN overexpression to induce neuroblastoma in mice and identified Ret as being strongly upregulated in MYCN/Alk(mu)t tumors. By a genetic approach in vivo, we now document an oncogenic cooperation between activated Ret and MYCN overexpression in neuroblastoma formation. We show that MYCN/Ret(M919T) tumors exhibit histological features and expression profiles close to MYCN/Alk(mut) tumors. We show that RET transcript levels decrease precedes RET protein levels decrease upon ALK inhibition in neuroblastoma cell lines. Etv5 was identified as a candidate transcription factor regulating Ret expression from murine MYCN/Alk(mut) tumor transcriptomic data. We demonstrate that ETV5 is regulated both at the protein and mRNA levels upon ALK activation or inhibition in neuroblastoma cell lines and that this regulation precedes RET modulation. We document that ALK activation induces ETV5 protein upregulation through stabilization in a MEK/ERK- dependent manner. We show that RNAi-mediated inhibition of ETV5 decreases RET expression. Reporter assays indicate that ETV5 is able to drive RET gene transcription. ChIP-seq analysis confirmed ETV5 binding on the RET promoter and identified an enhancer upstream of the promoter. Finally, we demonstrate that combining RET and ALK inhibitors reduces tumor growth more efficiently than each single agent in MYCN and Alk(F1178L)-driven murine neuroblastoma. Altogether, these results define the ERK-ETV5-RET pathway as a critical axis driving neuroblastoma oncogenesis downstream of activated ALK.
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