Journal Article

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

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

2024

Overview

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.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publication,eLife Sciences Publications, Ltd
• Subject: Activin Receptors, Type I - genetics / Activin Receptors, Type I - metabolism / Biochemistry, Molecular Biology / BMP / Bone morphogenetic protein 2 / Bone Morphogenetic Protein 2 - genetics / Bone Morphogenetic Protein 2 - metabolism / Bone Morphogenetic Protein 7 - genetics / Bone Morphogenetic Protein 7 - metabolism / Bone morphogenetic proteins / Brain cancer / Brain Neoplasms - genetics / Brain Neoplasms - metabolism / Brain Neoplasms - pathology / Brain tumors / Cancer / Cancer Biology / Cancer in children / Cancer invasiveness / Cell Line, Tumor / Child / Children / Development and progression / DMG / Epigenetic inheritance / Epigenetics / Gene expression / Gene Expression Regulation, Neoplastic / Gene mutations / Genetic aspects / Genetically modified organisms / Genomics / Glioma / Glioma - genetics / Glioma - metabolism / Glioma - pathology / Glioma cells / Gliomas / H3K27 mutation / Health aspects / Histone H3 / Histones / Histones - genetics / Histones - metabolism / Human health and pathology / Humans / invasion / Invasiveness / Life Sciences / Ligands / Mutation / Neoplasm Invasiveness / Neurobiology / Neurons and Cognition / Pediatric research / Pediatrics / Phenotypes / Principal components analysis / Proteins / Signal Transduction / Transcription factors / Transcriptomics / Tumorigenesis / Tumors