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Updated: Jun 11, 2025
Live-3D-Cell Immunocytochemistry Assays of Pediatric Diffuse Midline Glioma
Published on: November 11, 2021
BMP2 and BMP7 cooperate with H3.3K27M to promote quiescence and invasiveness in pediatric diffuse midline gliomas
Paul Huchede1, Swann Meyer1, Clément Berthelot1
1Childhood Cancer & Cell Death (C3) team, LabEx DEVweCAN, Institut Convergence Plascan, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Lyon, France.
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 K27M/BMP crosstalk.
Insights
Pediatric diffuse midline gliomas (pDMG) involve histone H3 K27M mutations. The BMP signaling pathway, activated by BMP2/7, synergizes with K27M to promote a quiescent yet invasive tumor state in pDMG.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Pediatric diffuse midline gliomas (pDMG) are aggressive childhood brain tumors with poor prognosis.
- Histone H3 K27M mutations are a key epigenetic driver, but other oncogenic mechanisms remain unclear.
- The BMP signaling pathway is altered in some pDMG due to ACVR1 mutations, but its role in ACVR1 wild-type tumors is less understood.
Purpose of the Study:
- To investigate the role of the BMP signaling pathway in pDMG, particularly in tumors without ACVR1 mutations.
- To identify specific BMP ligands involved in pDMG pathogenesis.
- To elucidate the synergistic interaction between H3.3K27M and BMP signaling.
Main Methods:
- Integration of bulk, single-cell, and spatial transcriptomic data.
- Analysis of pediatric isogenic glioma lines with H3.3K27M overexpression.
- Utilized patient-derived DIPG cell lines.
Main Results:
- The BMP signaling pathway is activated in both ACVR1 wild-type and mutant pDMG.
- BMP2 and BMP7 were identified as potential activators in specific cell subpopulations.
- BMP2/7 synergizes with H3.3K27M to induce transcriptomic changes associated with a quiescent, invasive cell phenotype.
Conclusions:
- The BMP signaling pathway plays a general oncogenic role in pDMG development.
- BMP2/7 and H3.3K27M cooperate to drive a pro-invasive tumor state.
- Targeting downstream effectors of the K27M/BMP crosstalk offers a potential therapeutic strategy for pDMG.
