Cargando…
MODL-02. A novelCre-conditionalcMYC-driven MB Group 3 transgenic mouse model shows traceable leptomeningeal dissemination.
Medulloblastoma (MB), the most common embryonal tumour of the Central Nervous System, occurs in the cerebellum. Treatment regimens involve surgery, craniospinal radiotherapy, and chemotherapy. The greatest mortality is associated with disseminated disease, almost exclusively found in the leptomening...
Autores principales: | , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9165051/ http://dx.doi.org/10.1093/neuonc/noac079.625 |
_version_ | 1784720294365102080 |
---|---|
author | Morcavallo, Alaide Barker, Karen Kwok, Colin Boult, Jessica K R da Silva, Patricia Benites Goncalves Okonechnikov, Konstantin Zuckermann, Marc Gorrini, Chiara Jacques, Thomas S Robinson, Simon P Clifford, Steven C Weiss, William A Pfister, Stefan M Kawauchi, Daisuke Chesler, Louis |
author_facet | Morcavallo, Alaide Barker, Karen Kwok, Colin Boult, Jessica K R da Silva, Patricia Benites Goncalves Okonechnikov, Konstantin Zuckermann, Marc Gorrini, Chiara Jacques, Thomas S Robinson, Simon P Clifford, Steven C Weiss, William A Pfister, Stefan M Kawauchi, Daisuke Chesler, Louis |
author_sort | Morcavallo, Alaide |
collection | PubMed |
description | Medulloblastoma (MB), the most common embryonal tumour of the Central Nervous System, occurs in the cerebellum. Treatment regimens involve surgery, craniospinal radiotherapy, and chemotherapy. The greatest mortality is associated with disseminated disease, almost exclusively found in the leptomeningeal space. Unfortunately, knowledge about the aetiology of MB spread is limited and the need for kinder and efficacious therapy remains an unmet goal. Of the four molecular classified MB groups, Group3 (Gr3) MB presents with a high frequency of metastasis at diagnosis, with the worst overall survival. Gr3 MB tumours are dominated by primitive progenitor-like cells and cMYC deregulation; often, p53 deficiency is observed at relapse. To dissect the biology of primary and metastatic Gr3 MB, we have developed a new germline genetically engineered mouse model (GEMM), harbouring cMYC amplification in a Tamoxifen-inducible p53 functional background (Trp53ERTAM strain). A novel LSL-cMYC-CopGFP-Luciferase transgene was integrated into the Rosa-26 locus of the mouse genome. Transgenic mice were crossed with a strain expressing Cre recombinase under the Blbp promoter targeting embryonic neural progenitors, and subsequently bred to Trp53ERTAM mice. As result, the cMYC overexpression was sufficient to generate tumours. Tumour penetrance was observed in all the expected tumour bearing genotypes, with increased aggressiveness in a non-functional p53 background. Bioluminescence imaging demonstrated tumour onset in the brain and dissemination along the spinal cord. CopGFP positive tumour cells were isolated from primary and metastatic tumours. Pathological interrogation confirmed that tumours present large cell/anaplastic (LCA) histology. Analysis of preliminary transcriptional profiling data proved that tumours cluster with human Gr3 MB. Ongoing methylation profiling and multi-omics approaches will inform on the tumour cells of origin and clonal divergence of primary tumour versus metastasis. In conclusion, we have successfully developed a novel immunocompetent mouse model of metastatic Gr3 MB with which we can investigate therapeutic vulnerabilities of MB. |
format | Online Article Text |
id | pubmed-9165051 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-91650512022-06-05 MODL-02. A novelCre-conditionalcMYC-driven MB Group 3 transgenic mouse model shows traceable leptomeningeal dissemination. Morcavallo, Alaide Barker, Karen Kwok, Colin Boult, Jessica K R da Silva, Patricia Benites Goncalves Okonechnikov, Konstantin Zuckermann, Marc Gorrini, Chiara Jacques, Thomas S Robinson, Simon P Clifford, Steven C Weiss, William A Pfister, Stefan M Kawauchi, Daisuke Chesler, Louis Neuro Oncol Preclinical Models/Experimental Therapy/Drug Discovery Medulloblastoma (MB), the most common embryonal tumour of the Central Nervous System, occurs in the cerebellum. Treatment regimens involve surgery, craniospinal radiotherapy, and chemotherapy. The greatest mortality is associated with disseminated disease, almost exclusively found in the leptomeningeal space. Unfortunately, knowledge about the aetiology of MB spread is limited and the need for kinder and efficacious therapy remains an unmet goal. Of the four molecular classified MB groups, Group3 (Gr3) MB presents with a high frequency of metastasis at diagnosis, with the worst overall survival. Gr3 MB tumours are dominated by primitive progenitor-like cells and cMYC deregulation; often, p53 deficiency is observed at relapse. To dissect the biology of primary and metastatic Gr3 MB, we have developed a new germline genetically engineered mouse model (GEMM), harbouring cMYC amplification in a Tamoxifen-inducible p53 functional background (Trp53ERTAM strain). A novel LSL-cMYC-CopGFP-Luciferase transgene was integrated into the Rosa-26 locus of the mouse genome. Transgenic mice were crossed with a strain expressing Cre recombinase under the Blbp promoter targeting embryonic neural progenitors, and subsequently bred to Trp53ERTAM mice. As result, the cMYC overexpression was sufficient to generate tumours. Tumour penetrance was observed in all the expected tumour bearing genotypes, with increased aggressiveness in a non-functional p53 background. Bioluminescence imaging demonstrated tumour onset in the brain and dissemination along the spinal cord. CopGFP positive tumour cells were isolated from primary and metastatic tumours. Pathological interrogation confirmed that tumours present large cell/anaplastic (LCA) histology. Analysis of preliminary transcriptional profiling data proved that tumours cluster with human Gr3 MB. Ongoing methylation profiling and multi-omics approaches will inform on the tumour cells of origin and clonal divergence of primary tumour versus metastasis. In conclusion, we have successfully developed a novel immunocompetent mouse model of metastatic Gr3 MB with which we can investigate therapeutic vulnerabilities of MB. Oxford University Press 2022-06-03 /pmc/articles/PMC9165051/ http://dx.doi.org/10.1093/neuonc/noac079.625 Text en © The Author(s) 2022. 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 | Preclinical Models/Experimental Therapy/Drug Discovery Morcavallo, Alaide Barker, Karen Kwok, Colin Boult, Jessica K R da Silva, Patricia Benites Goncalves Okonechnikov, Konstantin Zuckermann, Marc Gorrini, Chiara Jacques, Thomas S Robinson, Simon P Clifford, Steven C Weiss, William A Pfister, Stefan M Kawauchi, Daisuke Chesler, Louis MODL-02. A novelCre-conditionalcMYC-driven MB Group 3 transgenic mouse model shows traceable leptomeningeal dissemination. |
title | MODL-02. A novelCre-conditionalcMYC-driven MB Group 3 transgenic mouse model shows traceable leptomeningeal dissemination. |
title_full | MODL-02. A novelCre-conditionalcMYC-driven MB Group 3 transgenic mouse model shows traceable leptomeningeal dissemination. |
title_fullStr | MODL-02. A novelCre-conditionalcMYC-driven MB Group 3 transgenic mouse model shows traceable leptomeningeal dissemination. |
title_full_unstemmed | MODL-02. A novelCre-conditionalcMYC-driven MB Group 3 transgenic mouse model shows traceable leptomeningeal dissemination. |
title_short | MODL-02. A novelCre-conditionalcMYC-driven MB Group 3 transgenic mouse model shows traceable leptomeningeal dissemination. |
title_sort | modl-02. a novelcre-conditionalcmyc-driven mb group 3 transgenic mouse model shows traceable leptomeningeal dissemination. |
topic | Preclinical Models/Experimental Therapy/Drug Discovery |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9165051/ http://dx.doi.org/10.1093/neuonc/noac079.625 |
work_keys_str_mv | AT morcavalloalaide modl02anovelcreconditionalcmycdrivenmbgroup3transgenicmousemodelshowstraceableleptomeningealdissemination AT barkerkaren modl02anovelcreconditionalcmycdrivenmbgroup3transgenicmousemodelshowstraceableleptomeningealdissemination AT kwokcolin modl02anovelcreconditionalcmycdrivenmbgroup3transgenicmousemodelshowstraceableleptomeningealdissemination AT boultjessicakr modl02anovelcreconditionalcmycdrivenmbgroup3transgenicmousemodelshowstraceableleptomeningealdissemination AT dasilvapatriciabenitesgoncalves modl02anovelcreconditionalcmycdrivenmbgroup3transgenicmousemodelshowstraceableleptomeningealdissemination AT okonechnikovkonstantin modl02anovelcreconditionalcmycdrivenmbgroup3transgenicmousemodelshowstraceableleptomeningealdissemination AT zuckermannmarc modl02anovelcreconditionalcmycdrivenmbgroup3transgenicmousemodelshowstraceableleptomeningealdissemination AT gorrinichiara modl02anovelcreconditionalcmycdrivenmbgroup3transgenicmousemodelshowstraceableleptomeningealdissemination AT jacquesthomass modl02anovelcreconditionalcmycdrivenmbgroup3transgenicmousemodelshowstraceableleptomeningealdissemination AT robinsonsimonp modl02anovelcreconditionalcmycdrivenmbgroup3transgenicmousemodelshowstraceableleptomeningealdissemination AT cliffordstevenc modl02anovelcreconditionalcmycdrivenmbgroup3transgenicmousemodelshowstraceableleptomeningealdissemination AT weisswilliama modl02anovelcreconditionalcmycdrivenmbgroup3transgenicmousemodelshowstraceableleptomeningealdissemination AT pfisterstefanm modl02anovelcreconditionalcmycdrivenmbgroup3transgenicmousemodelshowstraceableleptomeningealdissemination AT kawauchidaisuke modl02anovelcreconditionalcmycdrivenmbgroup3transgenicmousemodelshowstraceableleptomeningealdissemination AT cheslerlouis modl02anovelcreconditionalcmycdrivenmbgroup3transgenicmousemodelshowstraceableleptomeningealdissemination |