The Intricate Epigenetic and Transcriptional Alterations in Pediatric High-Grade Gliomas: Targeting the Crosstalk as the Oncogenic Achilles’ Heel

Huchedé, Paul; Leblond, Pierre; Castets, Marie

doi:10.3390/biomedicines10061311

Cited by 9 publications

(2 citation statements)

References 179 publications

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“…pHGG, H3- and IDH-wt, and Infant-type DHG subtypes are reviewed in [ 32 , 35 , 36 ] and will not be discussed further here. We will primarily focus on H3 K27M mutations in DMG and the resulting epigenetic dysregulation of these tumors.…”

Section: Pediatric-type High-grade Gliomas (Phggs)mentioning

confidence: 99%

The Landscape of Pediatric High-Grade Gliomas: The Virtues and Pitfalls of Pre-Clinical Models

Furst,

Roussel,

Leung

et al. 2024

Biology

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Pediatric high-grade gliomas (pHGG) are malignant and usually fatal central nervous system (CNS) WHO Grade 4 tumors. The majority of pHGG consist of diffuse midline gliomas (DMG), H3.3 or H3.1 K27 altered, or diffuse hemispheric gliomas (DHG) (H3.3 G34-mutant). Due to diffuse tumor infiltration of eloquent brain areas, especially for DMG, surgery has often been limited and chemotherapy has not been effective, leaving fractionated radiation to the involved field as the current standard of care. pHGG has only been classified as molecularly distinct from adult HGG since 2012 through Next-Generation sequencing approaches, which have shown pHGG to be epigenetically regulated and specific tumor sub-types to be representative of dysregulated differentiating cells. To translate discovery research into novel therapies, improved pre-clinical models that more adequately represent the tumor biology of pHGG are required. This review will summarize the molecular characteristics of different pHGG sub-types, with a specific focus on histone K27M mutations and the dysregulated gene expression profiles arising from these mutations. Current and emerging pre-clinical models for pHGG will be discussed, including commonly used patient-derived cell lines and in vivo modeling techniques, encompassing patient-derived xenograft murine models and genetically engineered mouse models (GEMMs). Lastly, emerging techniques to model CNS tumors within a human brain environment using brain organoids through co-culture will be explored. As models that more reliably represent pHGG continue to be developed, targetable biological and genetic vulnerabilities in the disease will be more rapidly identified, leading to better treatments and improved clinical outcomes.

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Section: Pediatric-type High-grade Gliomas (Phggs)mentioning

confidence: 99%

The Landscape of Pediatric High-Grade Gliomas: The Virtues and Pitfalls of Pre-Clinical Models

Furst,

Roussel,

Leung

et al. 2024

Biology

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“…In addition to TP53, other genetic alterations have been described, notably in the PDGFR, EGFR or PIK3CA genes 1 , suggesting an oncogenic synergy between H3K27-based epigenetic remodeling and the activation of several transcriptional programs 18,19 . Accordingly, 20 to 30% of pDMG cases are associated with mutations in the ACVR1 gene, encoding for the bone morphogenetic protein (BMP) type I receptor ALK2 [20][21][22][23] , which leads to the overactivation of intracellular BMP signaling pathway [24][25][26][27][28][29][30][31][32] .…”

Section: Introductionmentioning

confidence: 99%

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

Huchedé,

Meyer,

Berthelot

et al. 2023

Preprint

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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.

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Cancers de l'enfant

Robert

2023

Ciblage Thérapeutique en Oncologie

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The Intricate Epigenetic and Transcriptional Alterations in Pediatric High-Grade Gliomas: Targeting the Crosstalk as the Oncogenic Achilles’ Heel

Cited by 9 publications

References 179 publications

The Landscape of Pediatric High-Grade Gliomas: The Virtues and Pitfalls of Pre-Clinical Models

The Landscape of Pediatric High-Grade Gliomas: The Virtues and Pitfalls of Pre-Clinical Models

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

Cancers de l'enfant

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