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

• DOI: 10.7554/elife.91313.1
• Publication Date: 2023-11-23T15:27:29Z
• Authors: Paul Huchedé; Swann Meyer; Clément Berthelot; Maud Hamadou; Adrien Bertrand-C...; Andria Rakotomalala; Line Manceau; Julia Tomine; Nicolas Lespinasse; Paul Lewandowski; Martine Cordier-B...; Laura Broutier; Aurélie Dutour; Isabelle Rochet; Jean-Yves Blay; Cyril Degletagne; Valéry Attignon; Angel Montero-Car...; Marion Le Grand; Eddy Pasquier; Alexandre Vasiljevic; Pascale Gilardi-H...; Samuel Meignan; Pierre Leblond; Vanessa Ribes; Erika Cosset; Marie Castets
• Keywords: 0301 basic medicine; QH301-705.5; [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology; Science; Bone Morphogenetic Protein 7; Bone Morphogenetic Protein 2; [SDV.CAN]Life Sciences [q-bio]/Cancer; Histones; DMG; 03 medical and health sciences; [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics; [SDV.CAN] Life Sciences [q-bio]/Cancer; [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN]; Cell Line, Tumor; BMP; Humans; Neoplasm Invasiveness; Biology (General); H3K27 mutation; Child; Cancer Biology; [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics; Brain Neoplasms; Q; [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology; R; Glioma; invasion; 3. Good health; Gene Expression Regulation, Neoplastic; Mutation; [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN]; Medicine; Activin Receptors, Type I; Signal Transduction

Abstract 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 BMP/K27M crosstalk.