METTL3/MYCN cooperation drives neural crest differentiation and provides therapeutic vulnerability in neuroblastoma
Neuroblastoma (NB) is the most common extracranial childhood cancer, caused by the improper differentiation of developing trunk neural crest cells (tNCC) in the sympathetic nervous system. The N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) epitranscriptomic modification controls post-transcriptional gene expression but the mechanism by which the m<sup>6</sup>A methyltransferase complex METTL3/METTL14/WTAP is recruited to specific loci remains to be fully characterized. We explored whether the m<sup>6</sup>A epitranscriptome could fine-tune gene regulation in migrating/differentiating tNCC. We demonstrate that the m<sup>6</sup>A modification regulates the expression of HOX genes in tNCC, thereby contributing to their timely differentiation into sympathetic neurons. Furthermore, we show that posterior HOX genes are m<sup>6</sup>A modified in MYCN-amplified NB with reduced expression. In addition, we provide evidence that sustained overexpression of the MYCN oncogene in tNCC drives METTL3 recruitment to a specific subset of genes including posterior HOX genes creating an undifferentiated state. Moreover, METTL3 depletion/inhibition induces DNA damage and differentiation of MYCN overexpressing cells and increases vulnerability to chemotherapeutic drugs in MYCN-amplified patient-derived xenografts (PDX) in vivo, suggesting METTL3 inhibition could be a potential therapeutic approach for NB.
Authors
- Rebeca Burgos‐Panadero (ORCID: https://orcid.org/0000-0003-0811-2675)
- Mohammad Hassan Baig (ORCID: https://orcid.org/0000-0001-8227-4838)
- Pekka Jaako (ORCID: https://orcid.org/0000-0003-3587-8318)
- John Inge Johnsen (ORCID: https://orcid.org/0000-0003-1277-812X)
- Roshan Vaid (ORCID: https://orcid.org/0000-0002-2074-5080)
- Jae-June Dong
- Stefanie Höppner (ORCID: https://orcid.org/0000-0002-2318-1874)
- Suzanne Dawn Turner (ORCID: https://orcid.org/0000-0002-8439-4507)
- Matthias Fischer (ORCID: https://orcid.org/0000-0003-1363-1242)
- Christoph Bartenhagen (ORCID: https://orcid.org/0000-0002-2522-1454)
- Sagar D. Nale (ORCID: https://orcid.org/0000-0002-6326-3188)
- Akram Mendez (ORCID: https://orcid.org/0000-0001-9195-3808)
- Ketan Thombare (ORCID: https://orcid.org/0000-0002-0183-3376)
- Per Kogner (ORCID: https://orcid.org/0000-0002-2202-9694)
- Tommy Martinsson (ORCID: https://orcid.org/0000-0002-9403-3123)
- Daniel Sjövall (ORCID: https://orcid.org/0000-0002-3491-2740)
- Anna Djos (ORCID: https://orcid.org/0000-0002-5250-2163)
- Kerstin Lundberg (ORCID: https://orcid.org/0009-0003-7099-0644)
- Tanmoy Mondal (ORCID: https://orcid.org/0000-0001-6228-8001)
- Perla Pucci (ORCID: https://orcid.org/0000-0003-1264-3487)
- Ritish Ayyalusamy (ORCID: https://orcid.org/0009-0003-8081-9357)
- Aqsa Ali Rehan (ORCID: https://orcid.org/0009-0008-9030-7992)
Institutions
- Karolinska University Hospital (SE)
- University of Cologne (DE)
- University of Cambridge (GB)
- Sahlgrenska University Hospital (SE)
- Ghent University Global Campus (KR)
- Gangnam Severance Hospital (KR)
- University Hospital Cologne (DE)
- University of Gothenburg (SE)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2024-11-11
- DOI
- https://doi.org/10.1038/s44318-024-00299-8
- Citations
- 5
- Primary Topic
- Neuroblastoma Research and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 1.85
Funders
- Åke Wiberg Stiftelse
- Kungl. Vetenskaps- och Vitterhets-Samhället i Göteborg
- Tore Nilsons Stiftelse för Medicinsk Forskning
- Cancerfonden
- Vetenskapsrådet
- Stiftelsen Assar Gabrielssons Fond
- Barncancerfonden
- Svenska Läkaresällskapet