BMP2 and BMP7 cooperate with H3.3K27M to promote quiescence and invasiveness in pediatric diffuse midline gliomas

Author:

Huchedé Paul,Meyer Swann,Berthelot Clément,Hamadou Maud,Bertrand-Chapel Adrien,Rakotomalala Andria,Manceau Line,Tomine Julia,Lespinasse Nicolas,Lewandowski Paul,Cordier-Bussat Martine,Broutier Laura,Dutour Aurélie,Rochet Isabelle,Blay Jean-YvesORCID,Degletagne Cyril,Attignon Valéry,Montero-Carcaboso Angel,Grand Marion Le,Pasquier Eddy,Vasiljevic Alexandre,Gilardi-Hebenstreit Pascale,Meignan Samuel,Leblond Pierre,Ribes VanessaORCID,Cosset Erika,Castets Marie

Abstract

AbstractPediatric 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 byACVR1.However, the potential impact of the BMP pathway in tumors non-mutated forACVR1is less clear. By integrating bulk, single-cell and spatial transcriptomic data, we show here that the BMP signaling pathway is activated at similar levels betweenACVR1wild 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 BMP/K27M crosstalk.

Publisher

Cold Spring Harbor Laboratory

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