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Bone Morphogenic Proteins in Pediatric Diffuse Midline Gliomas: How to Make New Out of Old?
Clément Berthelot1,2, Paul Huchedé1,2, Adrien Bertrand-Chapel1,2
1Childhood Cancer & Cell Death Team (C3 Team), LabEx DEVweCAN, Institut Convergence Plascan, Centre de Recherche en Cancérologie de Lyon (CRCL), Centre Léon Bérard, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, 69008 Lyon, France.
Abstract:
The BMP pathway is one of the major signaling pathways in embryonic development, ontogeny and homeostasis, identified many years ago by pioneers in developmental biology. Evidence of the deregulation of its activity has also emerged in many cancers, with complex and sometimes opposing effects. Recently, its role has been suspected in Diffuse Midline Gliomas (DMG), among which Diffuse Intrinsic Pontine Gliomas (DIPG) are one of the most complex challenges in pediatric oncology. Genomic sequencing has led to understanding part of their molecular etiology, with the identification of histone H3 mutations in a large proportion of patients. The epigenetic remodeling associated with these genetic alterations has also been precisely described, creating a permissive context for oncogenic transcriptional program activation. This review aims to describe the new findings about the involvement of BMP pathway activation in these tumors, placing their appearance in a developmental context. Targeting the oncogenic synergy resulting from this pathway activation in an H3K27M context could offer new therapeutic perspectives based on targeting treatment-resistant cell states.
Insights
Bone morphogenetic protein (BMP) pathway activation is implicated in Diffuse Midline Gliomas (DMG), particularly pediatric Diffuse Intrinsic Pontine Gliomas (DIPG). Targeting this pathway offers new therapeutic strategies for treatment-resistant cancer cells.
Area of Science:
- Developmental Biology
- Oncology
- Molecular Biology
Background:
- The BMP pathway is crucial for embryonic development and homeostasis.
- Deregulation of BMP signaling is linked to various cancers.
- Diffuse Midline Gliomas (DMG), including pediatric Diffuse Intrinsic Pontine Gliomas (DIPG), are challenging pediatric brain tumors.
Purpose of the Study:
- To review recent findings on BMP pathway activation in DMG.
- To contextualize the role of BMP signaling in tumor development.
- To explore therapeutic strategies targeting BMP pathway in H3K27M-mutated DMG.
Main Methods:
- Literature review of recent studies on BMP signaling in DMG.
- Analysis of genomic and epigenetic data related to H3K27M mutations.
- Integration of developmental biology principles with cancer research.
Main Results:
- BMP pathway activation is increasingly recognized in DMG pathogenesis.
- Histone H3 mutations (H3K27M) contribute to epigenetic alterations that promote oncogenesis.
- BMP pathway activation creates a permissive environment for tumor growth in an H3K27M context.
Conclusions:
- BMP pathway activation plays a significant role in the development of H3K27M-mutated DMG.
- Understanding this role within a developmental context is key.
- Targeting the interplay between BMP signaling and epigenetic changes may yield novel therapeutic approaches for resistant tumor states.
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