BMP2 and BMP7 cooperate with H3.3K27M to promote quiescence and invasiveness in pediatric diffuse midline gliomas
Pediatric diffuse midline gliomas (pDMG) are an aggressive type of childhood cancer with a fatal outcome. Their major epigenetic determinism has become clear, notably with the identification of K27M mutations in histone H3. However, the synergistic oncogenic mechanisms that induce and maintain tumor cell phenotype have yet to be deciphered. In 20 to 30% of cases, these tumors have an altered BMP signaling pathway with an oncogenic mutation on the BMP type I receptor ALK2, encoded by ACVR1 . However, the potential impact of the BMP pathway in tumors non-mutated for ACVR1 is less clear. By integrating bulk, single-cell, and spatial transcriptomic data, we show here that the BMP signaling pathway is activated at similar levels between ACVR1 wild-type and mutant tumors and identify BMP2 and BMP7 as putative activators of the pathway in a specific subpopulation of cells. By using both pediatric isogenic glioma lines genetically modified to overexpress H3.3K27M and patients-derived DIPG cell lines, we demonstrate that BMP2/7 synergizes with H3.3K27M to induce a transcriptomic rewiring associated with a quiescent but invasive cell state. These data suggest a generic oncogenic role for the BMP pathway in gliomagenesis of pDMG and pave the way for specific targeting of downstream effectors mediating the K27M/BMP crosstalk.
Authors
- Laura Broutier (ORCID: https://orcid.org/0000-0001-5163-5573)
- Cyril Dégletagne (ORCID: https://orcid.org/0000-0002-5363-2381)
- Line Manceau (ORCID: https://orcid.org/0000-0002-3087-4564)
- Marion Le Grand (ORCID: https://orcid.org/0000-0002-4910-1289)
- Isabelle Rochet
- Érika Cosset (ORCID: https://orcid.org/0000-0001-5481-6556)
- Martine Cordier–Bussat (ORCID: https://orcid.org/0000-0002-3513-8769)
- Alexandre Vasiljevic (ORCID: https://orcid.org/0000-0001-5954-0317)
- Marie Castets (ORCID: https://orcid.org/0000-0002-6758-0017)
- Adrien Bertrand‐Chapel (ORCID: https://orcid.org/0000-0002-0174-4162)
- Maud Hamadou
- Swann Meyer (ORCID: https://orcid.org/0000-0003-3736-4302)
- Jean‐Yves Blay (ORCID: https://orcid.org/0000-0001-7190-120X)
- Paul Huchedé
- Pascale Gilardi‐Hebenstreit (ORCID: https://orcid.org/0000-0003-3134-583X)
- Valéry Attignon (ORCID: https://orcid.org/0000-0002-1529-0595)
- Vanessa Ribes (ORCID: https://orcid.org/0000-0001-7016-9192)
- Aurélie Dutour (ORCID: https://orcid.org/0000-0001-5741-3576)
- Nicolas Lespinasse
- Eddy Pasquier (ORCID: https://orcid.org/0000-0003-2824-5002)
- Andria Rakotomalala (ORCID: https://orcid.org/0000-0002-6119-246X)
- Samuel Meignan (ORCID: https://orcid.org/0000-0002-9386-7978)
- Angel Montero-Carcaboso
- Clément Berthelot (ORCID: https://orcid.org/0009-0004-7687-625X)
- Julia Tomine
- Pierre Leblond (ORCID: https://orcid.org/0000-0002-7088-2614)
- Paul Lewandowski (ORCID: https://orcid.org/0000-0003-3495-9976)
Institutions
- Université Claude Bernard Lyon 1 (FR)
- Centre National de la Recherche Scientifique (FR)
- Hospital Sant Joan de Déu Barcelona (ES)
- Inserm (FR)
- Université Paris Cité (FR)
- Université de Lille (FR)
- Hôpital Femme Mère Enfant (FR)
- Institut d’Hématologie et d’Oncologie Pédiatrique (FR)
- Centre Léon Bérard (FR)
- Institut Jacques Monod (FR)
- Centre de Recherche en Cancérologie de Lyon (FR)
- Cancer Genomics Centre (NL)
- Centre Oscar Lambret (FR)
- Centre de Recherche en Cancérologie de Marseille (FR)
Publication Details
- Journal
- eLife
- Published
- 2024-10-07
- DOI
- https://doi.org/10.7554/elife.91313.3
- Citations
- 3
- Primary Topic
- Glioma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 1.31
Funders
- Agence Nationale de la Recherche
- Ligue Contre le Cancer
- Université Claude Bernard Lyon 1