Pathogenetic insights from novel mouse models for human epilepsy-associated developmental glioneuronal tumors
Pathogenetic insights from novel mouse models for human epilepsy-associated developmental glioneuronal tumors
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DissertationPrüfungsdatum
16.09.2022Datum der Veröffentlichung
21.09.2022Erstgutachter
Schoch McGovern, SusanneZweitgutachter
Huberfeld, GillesMetadaten
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Background: Developmental, biologically benign brain tumors associated with epilepsy represent a highly heterogeneous group of neoplasms and include glioneuronal and glial entities. Gangliogliomas (GGs) are most abundant in this group. BRAFV600E is highly frequent in GGs and activation of mTOR cascade signaling has been reported. Occasional malignant GG variants harbor mutated TP53. The improved understanding of the genetic basis and molecular alterations of developmental epilepsy associated brain tumors in concert with the availability of new transgenic techniques and large-scale omics approaches allows the integrated analyses of pathomechanisms of these neoplasms systematically in novel mouse models.
Aims: Thus, the present study aims to (1) develop and characterize in vivo tumor models for GGs recapitulating glioneuronal- and epilepsy-associated features, (2) understand their subsequent histogenesis and cellular composition, and (3) gain knowledge on mechanisms associated with altered excitability.
Results: The present data show that co-electroporation of the constitutively active Akt and mutant BRAFV600E transgenes in mouse neural precursors is required to induce lowgrade glioneuronal tumors, resembling histopathological features of human GGs including strong microglial infiltrates. These neoplasms arise clonally from a single precursor population, still capable to develop both neuronal and glial cells. Interestingly, the presence of only one transgene does not lead to GG development. Moreover, Trp53 deletion in this model leads to high-grade glioneuronal tumors with a more severe clinical outcome. Purely glial tumors resembling polymorphous low-grade neuroepithelial tumors of the young (PLNTYs) emerge from only BRAFV600E. Spontaneous spike evaluation reflected the highest intrinsic activity potential by tumors harboring both BRAFV600E and mTOR activation.
Conclusion: The combinatorial genetic architecture of BRAFV600E induced developmental brain tumors with PI3K/Akt/mTOR signaling and Trp53-loss determines not only the neuropathological characteristics but also key biological as well as functional features with implication for improving the clinical management of affected patients.
Aims: Thus, the present study aims to (1) develop and characterize in vivo tumor models for GGs recapitulating glioneuronal- and epilepsy-associated features, (2) understand their subsequent histogenesis and cellular composition, and (3) gain knowledge on mechanisms associated with altered excitability.
Results: The present data show that co-electroporation of the constitutively active Akt and mutant BRAFV600E transgenes in mouse neural precursors is required to induce lowgrade glioneuronal tumors, resembling histopathological features of human GGs including strong microglial infiltrates. These neoplasms arise clonally from a single precursor population, still capable to develop both neuronal and glial cells. Interestingly, the presence of only one transgene does not lead to GG development. Moreover, Trp53 deletion in this model leads to high-grade glioneuronal tumors with a more severe clinical outcome. Purely glial tumors resembling polymorphous low-grade neuroepithelial tumors of the young (PLNTYs) emerge from only BRAFV600E. Spontaneous spike evaluation reflected the highest intrinsic activity potential by tumors harboring both BRAFV600E and mTOR activation.
Conclusion: The combinatorial genetic architecture of BRAFV600E induced developmental brain tumors with PI3K/Akt/mTOR signaling and Trp53-loss determines not only the neuropathological characteristics but also key biological as well as functional features with implication for improving the clinical management of affected patients.
Klassifikation (DDC)
570 Biowissenschaften, BiologieCases Cunillera, Silvia: Pathogenetic insights from novel mouse models for human epilepsy-associated developmental glioneuronal tumors. - Bonn, 2022. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-68103
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-68103
@phdthesis{handle:20.500.11811/10282,
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-68103,
author = {{Silvia Cases Cunillera}},
title = {Pathogenetic insights from novel mouse models for human epilepsy-associated developmental glioneuronal tumors},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2022,
month = sep,
note = {Background: Developmental, biologically benign brain tumors associated with epilepsy represent a highly heterogeneous group of neoplasms and include glioneuronal and glial entities. Gangliogliomas (GGs) are most abundant in this group. BRAFV600E is highly frequent in GGs and activation of mTOR cascade signaling has been reported. Occasional malignant GG variants harbor mutated TP53. The improved understanding of the genetic basis and molecular alterations of developmental epilepsy associated brain tumors in concert with the availability of new transgenic techniques and large-scale omics approaches allows the integrated analyses of pathomechanisms of these neoplasms systematically in novel mouse models.
Aims: Thus, the present study aims to (1) develop and characterize in vivo tumor models for GGs recapitulating glioneuronal- and epilepsy-associated features, (2) understand their subsequent histogenesis and cellular composition, and (3) gain knowledge on mechanisms associated with altered excitability.
Results: The present data show that co-electroporation of the constitutively active Akt and mutant BRAFV600E transgenes in mouse neural precursors is required to induce lowgrade glioneuronal tumors, resembling histopathological features of human GGs including strong microglial infiltrates. These neoplasms arise clonally from a single precursor population, still capable to develop both neuronal and glial cells. Interestingly, the presence of only one transgene does not lead to GG development. Moreover, Trp53 deletion in this model leads to high-grade glioneuronal tumors with a more severe clinical outcome. Purely glial tumors resembling polymorphous low-grade neuroepithelial tumors of the young (PLNTYs) emerge from only BRAFV600E. Spontaneous spike evaluation reflected the highest intrinsic activity potential by tumors harboring both BRAFV600E and mTOR activation.
Conclusion: The combinatorial genetic architecture of BRAFV600E induced developmental brain tumors with PI3K/Akt/mTOR signaling and Trp53-loss determines not only the neuropathological characteristics but also key biological as well as functional features with implication for improving the clinical management of affected patients.},
url = {https://hdl.handle.net/20.500.11811/10282}
}
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-68103,
author = {{Silvia Cases Cunillera}},
title = {Pathogenetic insights from novel mouse models for human epilepsy-associated developmental glioneuronal tumors},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2022,
month = sep,
note = {Background: Developmental, biologically benign brain tumors associated with epilepsy represent a highly heterogeneous group of neoplasms and include glioneuronal and glial entities. Gangliogliomas (GGs) are most abundant in this group. BRAFV600E is highly frequent in GGs and activation of mTOR cascade signaling has been reported. Occasional malignant GG variants harbor mutated TP53. The improved understanding of the genetic basis and molecular alterations of developmental epilepsy associated brain tumors in concert with the availability of new transgenic techniques and large-scale omics approaches allows the integrated analyses of pathomechanisms of these neoplasms systematically in novel mouse models.
Aims: Thus, the present study aims to (1) develop and characterize in vivo tumor models for GGs recapitulating glioneuronal- and epilepsy-associated features, (2) understand their subsequent histogenesis and cellular composition, and (3) gain knowledge on mechanisms associated with altered excitability.
Results: The present data show that co-electroporation of the constitutively active Akt and mutant BRAFV600E transgenes in mouse neural precursors is required to induce lowgrade glioneuronal tumors, resembling histopathological features of human GGs including strong microglial infiltrates. These neoplasms arise clonally from a single precursor population, still capable to develop both neuronal and glial cells. Interestingly, the presence of only one transgene does not lead to GG development. Moreover, Trp53 deletion in this model leads to high-grade glioneuronal tumors with a more severe clinical outcome. Purely glial tumors resembling polymorphous low-grade neuroepithelial tumors of the young (PLNTYs) emerge from only BRAFV600E. Spontaneous spike evaluation reflected the highest intrinsic activity potential by tumors harboring both BRAFV600E and mTOR activation.
Conclusion: The combinatorial genetic architecture of BRAFV600E induced developmental brain tumors with PI3K/Akt/mTOR signaling and Trp53-loss determines not only the neuropathological characteristics but also key biological as well as functional features with implication for improving the clinical management of affected patients.},
url = {https://hdl.handle.net/20.500.11811/10282}
}
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