A novel mouse model of diffuse midline glioma initiated in neonatal oligodendrocyte progenitor cells highlights cell‐of‐origin dependent effects of <scp>H3K27M</scp>

Tomita, Yusuke; Shimazu, Yosuke; Somasundaram, Agila; Tanaka, Yoshihiro; Takata, Nozomu; Ishi, Yukitomo; Gadd, Samantha; Hashizume, Rintaro; Angione, Angelo; Piñero, Gonzalo; Hambardzumyan, Dolores; Brat, Daniel J.; Hoeman, Christine; Becher, Oren J.

doi:10.1002/glia.24189

Cited by 19 publications

(11 citation statements)

References 44 publications

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“…Interestingly, these cells have in the past been hypothesized to be tumor precursor cells for other primary brain tumor types. However, subsequent study has not always been consistent with this hypothesis [ 80 ]. Within our study, we saw this effect.…”

Section: Discussionmentioning

confidence: 99%

Ganglioglioma deep transcriptomics reveals primitive neuroectoderm neural precursor-like population

Regal

Garcia

Jain

et al. 2023

acta neuropathol commun

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Gangliogliomas are brain tumors composed of neuron-like and macroglia-like components that occur in children and young adults. Gangliogliomas are often characterized by a rare population of immature astrocyte-appearing cells expressing CD34, a marker expressed in the neuroectoderm (neural precursor cells) during embryogenesis. New insights are needed to refine tumor classification and to identify therapeutic approaches. We evaluated five gangliogliomas with single nucleus RNA-seq, cellular indexing of transcriptomes and epitopes by sequencing, and/or spatially-resolved RNA-seq. We uncovered a population of CD34+ neoplastic cells with mixed neuroectodermal, immature astrocyte, and neuronal markers. Gene regulatory network interrogation in these neuroectoderm-like cells revealed control of transcriptional programming by TCF7L2/MEIS1-PAX6 and SOX2, similar to that found during neuroectodermal/neural development. Developmental trajectory analyses place neuroectoderm-like tumor cells as precursor cells that give rise to neuron-like and macroglia-like neoplastic cells. Spatially-resolved transcriptomics revealed a neuroectoderm-like tumor cell niche with relative lack of vascular and immune cells. We used these high resolution results to deconvolute clinically-annotated transcriptomic data, confirming that CD34+ cell-associated gene programs associate with gangliogliomas compared to other glial brain tumors. Together, these deep transcriptomic approaches characterized a ganglioglioma cellular hierarchy—confirming CD34+ neuroectoderm-like tumor precursor cells, controlling transcription programs, cell signaling, and associated immune cell states. These findings may guide tumor classification, diagnosis, prognostication, and therapeutic investigations.

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Section: Discussionmentioning

confidence: 99%

Ganglioglioma deep transcriptomics reveals primitive neuroectoderm neural precursor-like population

Regal

Garcia

Jain

et al. 2023

acta neuropathol commun

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show abstract

Section: Discussionmentioning

confidence: 89%

Ganglioglioma deep transcriptomics reveals primitive neuroectoderm neural precursor-like population

Regal

Garcia

Jain

et al. 2022

Preprint

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Gangliogliomas are brain tumors composed of neuron-like and macroglia-like components that occur in children and young adults. Gangliogliomas are often characterized by a rare population of immature astrocyte-appearing cells expressing CD34, a marker expressed in the neuroectoderm (neural precursor cells) during embryogenesis. New insights are needed to refine tumor classification and to identify therapeutic approaches. We evaluated five gangliogliomas with single nucleus RNA-seq, cellular indexing of transcriptomes and epitopes by sequencing, and/or spatially-resolved RNA-seq. We uncovered a population of CD34-rich neoplastic cells with mixed neuroectodermal, immature astrocyte, and neuronal markers. Gene regulatory network interrogation in these neuroectoderm-like cells revealed control of transcriptional programming by TCF7L2/MEIS1-PAX6 and SOX2, similar to that found during neuroectodermal/neural development. Developmental trajectory analyses place neuroectoderm-like tumor cells as precursor cells that give rise to neuron-like and macroglia-like neoplastic cells. Spatially-resolved transcriptomics revealed a neuroectoderm-like tumor cell niche with relative lack of vascular and immune cells. We used these high resolution results to deconvolute clinically-annotated transcriptomic data, confirming that CD34+ cell-associated gene programs associate with gangliogliomas compared to other glial brain tumors. Together, these deep transcriptomic approaches characterized a ganglioglioma cellular hierarchy - confirming CD34+ neuroectoderm-like tumor precursor cells, controlling transcription programs, cell signaling, and associated immune cell state. These findings may guide ganglioglioma tumor classification, diagnosis, and therapeutic investigations.

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“…Thus, an important open question is whether ATM loss radiosensitizes brainstem gliomas of different genotypes that also harbor H3K27M. We previously introduced H3K27M to brainstem glioma mouse models via RCAS-H3K27M viral transduction [ 16 , 27 , 31 ]. For the present investigation, we similarly attempted to introduce H3K27M via RCAS-H3K27M virus transduction along with the RCAS-luciferase, RCAS-Cre, and RCAS-PDGF-B vectors (four total RCAS viruses).…”

Section: Discussionmentioning

confidence: 99%

“…However, we observed variable and low levels of tumoral H3K27M expression in these attempts (data not shown). Our previous studies achieved high H3K27M expression penetrance when H3K27M was introduced alongside only RCAS-PDGF-B with or without RCAS-Cre (two to three RCAS viruses) [ 16 , 27 , 31 ]; critically, these prior studies did not rely on RCAS-luciferase. We speculate that the lower H3K27M penetrance in the present attempts may reflect diminished transduction efficiency when four or more RCAS viruses are introduced to the mouse brainstem.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Atm Loss on Radiosensitivity of a Primary Mouse Model of Pten-Deleted Brainstem Glioma

Stewart

Guerra-García

Luo

et al. 2022

Cancers

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Diffuse midline gliomas arise in the brainstem and other midline brain structures and cause a large proportion of childhood brain tumor deaths. Radiation therapy is the most effective treatment option, but these tumors ultimately progress. Inhibition of the phosphoinositide-3-kinase (PI3K)-like kinase, ataxia–telangiectasia mutated (ATM), which orchestrates the cellular response to radiation-induced DNA damage, may enhance the efficacy of radiation therapy. Diffuse midline gliomas in the brainstem contain loss-of-function mutations in the tumor suppressor PTEN, or functionally similar alterations in the phosphoinositide-3-kinase (PI3K) pathway, at moderate frequency. Here, we sought to determine if ATM inactivation could radiosensitize a primary mouse model of brainstem glioma driven by Pten loss. Using Cre/loxP recombinase technology and the RCAS/TVA retroviral gene delivery system, we established a mouse model of brainstem glioma driven by Pten deletion. We find that Pten-null brainstem gliomas are relatively radiosensitive at baseline. In addition, we show that deletion of Atm in the tumor cells does not extend survival of mice bearing Pten-null brainstem gliomas after focal brain irradiation. These results characterize a novel primary mouse model of PTEN-mutated brainstem glioma and provide insights into the mechanism of radiosensitization by ATM deletion, which may guide the design of future clinical trials.

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A novel mouse model of diffuse midline glioma initiated in neonatal oligodendrocyte progenitor cells highlights cell‐of‐origin dependent effects of H3K27M

Cited by 19 publications

References 44 publications

Ganglioglioma deep transcriptomics reveals primitive neuroectoderm neural precursor-like population

Ganglioglioma deep transcriptomics reveals primitive neuroectoderm neural precursor-like population

Ganglioglioma deep transcriptomics reveals primitive neuroectoderm neural precursor-like population

The Effect of Atm Loss on Radiosensitivity of a Primary Mouse Model of Pten-Deleted Brainstem Glioma

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