Diffuse Intrinsic Pontine Gliomas Exhibit Cell Biological and Molecular Signatures of Fetal Hindbrain-Derived Neural Progenitor Cells

Sun, Yu; Xu, Changwu; Pan, Changcun; Chen, Xin; Geng, Yibo; Wu, Yadong; Zhang, Peng; Wu, Wenhao; Yü, Wang; Li, Deling; Wu, Zhen; Zhang, Junting; Xi, Qiaoran; Zhang, Liwei

doi:10.1007/s12264-018-00329-6

Cited by 11 publications

(7 citation statements)

References 26 publications

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“…The primary PPC cell lines were established as previously reported [24]. In brief, aborted human embryos (9–12 weeks) of either sex were obtained from Beijing Tiantan Hospital.…”

Section: Methodsmentioning

confidence: 99%

Potent anti-tumor efficacy of palbociclib in treatment-naïve H3.3K27M-mutant diffuse intrinsic pontine glioma

Sun

Yan

et al. 2019

EBioMedicine

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Background Diffuse intrinsic pontine glioma (DIPG) is a rare and fatal pediatric brain cancer without cure. Seeking therapeutic strategies is still a major challenge in DIPG research. Previous study has shown that dysregulation of G1/S cell cycle checkpoint was common in DIPG and this dysregulation is even more enriched in the H3.3K27 M mutant subgroup. Here we assess potential anti-tumor efficacy of palbociclib, a specific and cytostatic inhibitor of CDK4/6, on high grade H3.3-K27 M-mutant DIPGs in vitro and in vivo . Methods We established patient-derived cell lines from treatment-naïve specimens. All the lines have H3.3K27 M mutation. We used a range of biological in vitro assays to assess the effect of palbociclib on growth of DIPGs. Palbociclib activity was also assayed in vivo against three independent DIPG orthotropic xenografts model. Findings Dysregulation of G1/S cell cycle checkpoint is enriched in these DIPGs. Then, we showed that depletion of CDK4 or CDK6 inhibits DIPG cells growth and blocks G1/S transition. Furthermore, palbociclib effectively repressed DIPG growth in vitro . Transcriptome analysis showed that palbociclib not only blocks G1/S transition, it also blocks other oncogenic targets such as MYC. Finally, palbociclib activity was assayed in vivo against DIPG orthotropic xenografts to demonstrate the high efficiency of blocking tumor growth. Interpretation Our findings thus revealed that palbociclib could be the therapeutic strategy for treatment-naïve DIPG with H3.3K27 M mutation. Fund Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support, Beijing Municipal Natural Science Foundation, Ministry of Science and Technology of China, and National Natural Science Foundation of China.

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“…The primary PPC cell lines were established as previously reported [24]. In brief, aborted human embryos (9–12 weeks) of either sex were obtained from Beijing Tiantan Hospital.…”

Section: Methodsmentioning

confidence: 99%

Potent anti-tumor efficacy of palbociclib in treatment-naïve H3.3K27M-mutant diffuse intrinsic pontine glioma

Sun

Yan

et al. 2019

EBioMedicine

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“…In diffuse intrinsic pontine glioma (DIPG), nearly 80% of cases have a missense mutation in the histone 3.3 gene (H3F3A), causing a substitution of methionine for lysine 27 (H3K27M) (Khuong-Quang et al, 2012;Schwartzentruber et al, 2012;Wu et al, 2012). The origin of DIPG was indicated to lie in early neural development (Filbin et al, 2018;Sun et al, 2019), presumably making NPCs derived from ESCs a suitable model for tumor initiation. In line with this, overexpression of the H3K27M mutant in NPCs resulted in increased proliferation (Funato et al, 2014).…”

Section: Pluripotent Stem Cell-derived Cell Linesmentioning

confidence: 99%

In vitro Modeling of Embryonal Tumors

Custers

Paassen

Drost

2021

Front. Cell Dev. Biol.

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A subset of pediatric tumors affects very young children and are thought to arise during fetal life. A common theme is that these embryonal tumors hijack developmental programs, causing a block in differentiation and, as a consequence, unrestricted proliferation. Embryonal tumors, therefore typically maintain an embryonic gene signature not found in their differentiated progeny. Still, the processes underpinning malignant transformation remain largely unknown, which is hampering therapeutic innovation. To gain more insight into these processes, in vitro and in vivo research models are indispensable. However, embryonic development is an extremely dynamic process with continuously changing cellular identities, making it challenging to define cells-of-origin. This is crucial for the development of representative models, as targeting the wrong cell or targeting a cell within an incorrect developmental time window can result in completely different phenotypes. Recent innovations in in vitro cell models may provide more versatile platforms to study embryonal tumors in a scalable manner. In this review, we outline different in vitro models that can be explored to study embryonal tumorigenesis and for therapy development.

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“…While both neural stem/progenitor cells and early oligodendrocyte precursor cells have been capable of tumor formation in different experimental models, elegant work comparing the resultant epigenomic remodeling has revealed disparate chromatin patterning in these two contexts, with the active chromatin landscape of transformed OPCs more closely resembling that of DMG tumors [ 71 ]. The geography of these transformed cells also plays a role, as hindbrain precursor cells seem preferentially susceptible to transformation by H3.3K27M [ 23 , 72 ]. This geographic predilection is supported by dysregulation of H3K27 methylation in other pediatric hindbrain tumors such as subsets of medulloblastoma [ 73 ] and posterior fossa ependymoma [ 74 , 75 , 76 ].…”

Section: Molecular Mechanisms Of Oncogenicitymentioning

confidence: 99%

Histone-Mutant Glioma: Molecular Mechanisms, Preclinical Models, and Implications for Therapy

Graham

Mellinghoff

2020

IJMS

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Pediatric high-grade glioma (pHGG) is the leading cause of cancer death in children. Despite histologic similarities, it has recently become apparent that this disease is molecularly distinct from its adult counterpart. Specific hallmark oncogenic histone mutations within pediatric malignant gliomas divide these tumors into subgroups with different neuroanatomic and chronologic predilections. In this review, we will summarize the characteristic molecular alterations of pediatric high-grade gliomas, with a focus on how preclinical models of these alterations have furthered our understanding of their oncogenicity as well as their potential impact on developing targeted therapies for this devastating disease.

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Diffuse Intrinsic Pontine Gliomas Exhibit Cell Biological and Molecular Signatures of Fetal Hindbrain-Derived Neural Progenitor Cells

Cited by 11 publications

References 26 publications

Potent anti-tumor efficacy of palbociclib in treatment-naïve H3.3K27M-mutant diffuse intrinsic pontine glioma

Potent anti-tumor efficacy of palbociclib in treatment-naïve H3.3K27M-mutant diffuse intrinsic pontine glioma

In vitro Modeling of Embryonal Tumors

Histone-Mutant Glioma: Molecular Mechanisms, Preclinical Models, and Implications for Therapy

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