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BIOL-03. NOVEL GENETICALLY ENGINEERED MOUSE MODEL FOR CHOROID PLEXUS CARCINOMA MIMICS HUMAN DISEASE

Choroid plexus carcinomas (CPCs) are rare, aggressive malignant tumours of the central nervous system occurring mainly in children under the age of one. While advances in clinical and molecular stratification have enabled risk-adapted treatment planning and improvements in outcome for many types of...

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Autores principales: Duarte, Matilde de Almeida, Gilbertson, Richard, Taylor, Jessica, Jassim, Amir, Hu, Linda
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10259974/
http://dx.doi.org/10.1093/neuonc/noad073.022
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author Duarte, Matilde de Almeida
Gilbertson, Richard
Taylor, Jessica
Jassim, Amir
Hu, Linda
author_facet Duarte, Matilde de Almeida
Gilbertson, Richard
Taylor, Jessica
Jassim, Amir
Hu, Linda
author_sort Duarte, Matilde de Almeida
collection PubMed
description Choroid plexus carcinomas (CPCs) are rare, aggressive malignant tumours of the central nervous system occurring mainly in children under the age of one. While advances in clinical and molecular stratification have enabled risk-adapted treatment planning and improvements in outcome for many types of childhood brain tumours, there has not been equivalent progress for children with CPC. This has largely been due to the low incidence, leading treatment strategies to be mostly based on case series and a “standard of care” has yet to be established. In order to elucidate a coordinated therapeutic strategy for children with CPC, it is imperative to develop in vitro and in vivo models to improve our understanding of the mechanisms underlying tumorigenesis. We hypothesised that we could develop a genetically engineered mouse model (GEMM) to recapitulate patient CPCs, allowing for an early age of onset and high penetrance rate for accurate and efficient preclinical studies. To develop this GEMM of CPC, we utilized Cre-Lox technology to target CPC cells of origin. We crossed mice that conditionally expressed Tp53 (flx/flx); Rb (flx/flx); Pten (flx/flx) with mice harbouring a Tg((Ttr-cre/Esr1*)1Vco) allele, as it drives selective Cre-recombination in the early embryonic choroid plexus. Using this methodology, we have managed to produce CPCs within 90 days and with a 95% penetrance rate which we characterised using our laboratory’s tumour characterisation pipeline comprising histological evaluation, transcriptome analysis and imaging. We then used this model to investigate the transformation of the choroid during tumorigenesis and test novel therapeutic approaches to improve outcomes for patients affected by CPC. Not only are we looking for a “standard of care” that is currently inexistent for CPC, but we are also looking for one that will have minimal side effects and, therefore, not jeopardise the future of these children.
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spelling pubmed-102599742023-06-13 BIOL-03. NOVEL GENETICALLY ENGINEERED MOUSE MODEL FOR CHOROID PLEXUS CARCINOMA MIMICS HUMAN DISEASE Duarte, Matilde de Almeida Gilbertson, Richard Taylor, Jessica Jassim, Amir Hu, Linda Neuro Oncol Final Category: Basic Biology/Stem Cells/Models - BIOL Choroid plexus carcinomas (CPCs) are rare, aggressive malignant tumours of the central nervous system occurring mainly in children under the age of one. While advances in clinical and molecular stratification have enabled risk-adapted treatment planning and improvements in outcome for many types of childhood brain tumours, there has not been equivalent progress for children with CPC. This has largely been due to the low incidence, leading treatment strategies to be mostly based on case series and a “standard of care” has yet to be established. In order to elucidate a coordinated therapeutic strategy for children with CPC, it is imperative to develop in vitro and in vivo models to improve our understanding of the mechanisms underlying tumorigenesis. We hypothesised that we could develop a genetically engineered mouse model (GEMM) to recapitulate patient CPCs, allowing for an early age of onset and high penetrance rate for accurate and efficient preclinical studies. To develop this GEMM of CPC, we utilized Cre-Lox technology to target CPC cells of origin. We crossed mice that conditionally expressed Tp53 (flx/flx); Rb (flx/flx); Pten (flx/flx) with mice harbouring a Tg((Ttr-cre/Esr1*)1Vco) allele, as it drives selective Cre-recombination in the early embryonic choroid plexus. Using this methodology, we have managed to produce CPCs within 90 days and with a 95% penetrance rate which we characterised using our laboratory’s tumour characterisation pipeline comprising histological evaluation, transcriptome analysis and imaging. We then used this model to investigate the transformation of the choroid during tumorigenesis and test novel therapeutic approaches to improve outcomes for patients affected by CPC. Not only are we looking for a “standard of care” that is currently inexistent for CPC, but we are also looking for one that will have minimal side effects and, therefore, not jeopardise the future of these children. Oxford University Press 2023-06-12 /pmc/articles/PMC10259974/ http://dx.doi.org/10.1093/neuonc/noad073.022 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Final Category: Basic Biology/Stem Cells/Models - BIOL
Duarte, Matilde de Almeida
Gilbertson, Richard
Taylor, Jessica
Jassim, Amir
Hu, Linda
BIOL-03. NOVEL GENETICALLY ENGINEERED MOUSE MODEL FOR CHOROID PLEXUS CARCINOMA MIMICS HUMAN DISEASE
title BIOL-03. NOVEL GENETICALLY ENGINEERED MOUSE MODEL FOR CHOROID PLEXUS CARCINOMA MIMICS HUMAN DISEASE
title_full BIOL-03. NOVEL GENETICALLY ENGINEERED MOUSE MODEL FOR CHOROID PLEXUS CARCINOMA MIMICS HUMAN DISEASE
title_fullStr BIOL-03. NOVEL GENETICALLY ENGINEERED MOUSE MODEL FOR CHOROID PLEXUS CARCINOMA MIMICS HUMAN DISEASE
title_full_unstemmed BIOL-03. NOVEL GENETICALLY ENGINEERED MOUSE MODEL FOR CHOROID PLEXUS CARCINOMA MIMICS HUMAN DISEASE
title_short BIOL-03. NOVEL GENETICALLY ENGINEERED MOUSE MODEL FOR CHOROID PLEXUS CARCINOMA MIMICS HUMAN DISEASE
title_sort biol-03. novel genetically engineered mouse model for choroid plexus carcinoma mimics human disease
topic Final Category: Basic Biology/Stem Cells/Models - BIOL
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10259974/
http://dx.doi.org/10.1093/neuonc/noad073.022
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