Characterization of the spectrum of trivalent VAV1-mutation-driven tumours using a gene-edited mouse model

Mutations in the VAV1 guanine nucleotide exchange factor 1 have been recently found in peripheral T cell lymphoma and nonsmall-cell lung cancer (NSCLC). To understand their pathogenic potential, we generated a gene-edited mouse model that expresses a VAV1 mutant protein that recapitulates the signal...

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Autores: Robles-Valero, Javier, Fernández-Nevado, Lucía, Cuadrado, Myriam, Lorenzo-Martín, L. Francisco, Fernández-Pisonero, Isabel, Abad, Antonio, Redín, Esther, Montuenga, Luis, Martín-Zanca, Dionisio, Bigas Salvans, Anna, Mallo, Moises, Dosil, Mercedes, Bustelo, Xose R.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/55662
Acceso en línea:http://hdl.handle.net/10230/55662
http://dx.doi.org/10.1002/1878-0261.13295
Access Level:acceso abierto
Palabra clave:RAC1
TP53
Angioimmunoblastic T cell lymphoma
Follicular helper T cells
Nonsmall-cell lung cancer
Peripheral T cell lymphoma
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spelling Characterization of the spectrum of trivalent VAV1-mutation-driven tumours using a gene-edited mouse modelRobles-Valero, JavierFernández-Nevado, LucíaCuadrado, MyriamLorenzo-Martín, L. FranciscoFernández-Pisonero, IsabelAbad, AntonioRedín, EstherMontuenga, LuisMartín-Zanca, DionisioBigas Salvans, AnnaMallo, MoisesDosil, MercedesBustelo, Xose R.RAC1TP53Angioimmunoblastic T cell lymphomaFollicular helper T cellsNonsmall-cell lung cancerPeripheral T cell lymphomaMutations in the VAV1 guanine nucleotide exchange factor 1 have been recently found in peripheral T cell lymphoma and nonsmall-cell lung cancer (NSCLC). To understand their pathogenic potential, we generated a gene-edited mouse model that expresses a VAV1 mutant protein that recapitulates the signalling alterations present in the VAV1 mutant subclass most frequently found in tumours. We could not detect any overt tumourigenic process in those mice. However, the concurrent elimination of the Trp53 tumour suppressor gene in them drives T cell lymphomagenesis. This process represents an exacerbation of the normal functions that wild-type VAV1 plays in follicular helper T cells. We also found that, in combination with the Kras oncogene, the VAV1 mutant version favours progression of NSCLC. These data indicate that VAV1 mutations play critical, although highly cell-type-specific, roles in tumourigenesis. They also indicate that such functions are contingent on the mutational landscape of the tumours involved.We thank M.C. García-Macías and the personnel of both the CIC Flow Cytometry and Genomics Units for expert histological analyses, cell characterization and microarray work, respectively. The XRB's project leading to these results has received funding from the RTI2018-096481-B-100 grant cofounded by MCIN/AEI/10.13039/501100011033 and the European Research Development Fund “A way of making Europe”, the Spanish Association against Cancer (GC16173472GARC), the Castilla-León autonomous government (CSI252P18, CSI145P20, CLC-2017-01), and “la Caixa” Banking Foundation (HR20-00164). XRB's institution is supported by the Programa de Apoyo a Planes Estratégicos de Investigación de Estructuras de Investigación de Excelencia of the Castilla-León autonomous government (CLC-2017-01), JR-V received funding from the Carlos III Health Institute (PI20/01724). LF-N contract has been supported by the Salamanca local section of the Spanish Association against Cancer.Wiley202320232022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/55662http://dx.doi.org/10.1002/1878-0261.13295reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésMol Oncol. 2022 Oct;16(19):3533-53info:eu-repo/grantAgreement/ES/2PE/RTI2018-096481-B-100© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/556622026-06-12T07:21:37Z
dc.title.none.fl_str_mv Characterization of the spectrum of trivalent VAV1-mutation-driven tumours using a gene-edited mouse model
title Characterization of the spectrum of trivalent VAV1-mutation-driven tumours using a gene-edited mouse model
spellingShingle Characterization of the spectrum of trivalent VAV1-mutation-driven tumours using a gene-edited mouse model
Robles-Valero, Javier
RAC1
TP53
Angioimmunoblastic T cell lymphoma
Follicular helper T cells
Nonsmall-cell lung cancer
Peripheral T cell lymphoma
title_short Characterization of the spectrum of trivalent VAV1-mutation-driven tumours using a gene-edited mouse model
title_full Characterization of the spectrum of trivalent VAV1-mutation-driven tumours using a gene-edited mouse model
title_fullStr Characterization of the spectrum of trivalent VAV1-mutation-driven tumours using a gene-edited mouse model
title_full_unstemmed Characterization of the spectrum of trivalent VAV1-mutation-driven tumours using a gene-edited mouse model
title_sort Characterization of the spectrum of trivalent VAV1-mutation-driven tumours using a gene-edited mouse model
dc.creator.none.fl_str_mv Robles-Valero, Javier
Fernández-Nevado, Lucía
Cuadrado, Myriam
Lorenzo-Martín, L. Francisco
Fernández-Pisonero, Isabel
Abad, Antonio
Redín, Esther
Montuenga, Luis
Martín-Zanca, Dionisio
Bigas Salvans, Anna
Mallo, Moises
Dosil, Mercedes
Bustelo, Xose R.
author Robles-Valero, Javier
author_facet Robles-Valero, Javier
Fernández-Nevado, Lucía
Cuadrado, Myriam
Lorenzo-Martín, L. Francisco
Fernández-Pisonero, Isabel
Abad, Antonio
Redín, Esther
Montuenga, Luis
Martín-Zanca, Dionisio
Bigas Salvans, Anna
Mallo, Moises
Dosil, Mercedes
Bustelo, Xose R.
author_role author
author2 Fernández-Nevado, Lucía
Cuadrado, Myriam
Lorenzo-Martín, L. Francisco
Fernández-Pisonero, Isabel
Abad, Antonio
Redín, Esther
Montuenga, Luis
Martín-Zanca, Dionisio
Bigas Salvans, Anna
Mallo, Moises
Dosil, Mercedes
Bustelo, Xose R.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv RAC1
TP53
Angioimmunoblastic T cell lymphoma
Follicular helper T cells
Nonsmall-cell lung cancer
Peripheral T cell lymphoma
topic RAC1
TP53
Angioimmunoblastic T cell lymphoma
Follicular helper T cells
Nonsmall-cell lung cancer
Peripheral T cell lymphoma
description Mutations in the VAV1 guanine nucleotide exchange factor 1 have been recently found in peripheral T cell lymphoma and nonsmall-cell lung cancer (NSCLC). To understand their pathogenic potential, we generated a gene-edited mouse model that expresses a VAV1 mutant protein that recapitulates the signalling alterations present in the VAV1 mutant subclass most frequently found in tumours. We could not detect any overt tumourigenic process in those mice. However, the concurrent elimination of the Trp53 tumour suppressor gene in them drives T cell lymphomagenesis. This process represents an exacerbation of the normal functions that wild-type VAV1 plays in follicular helper T cells. We also found that, in combination with the Kras oncogene, the VAV1 mutant version favours progression of NSCLC. These data indicate that VAV1 mutations play critical, although highly cell-type-specific, roles in tumourigenesis. They also indicate that such functions are contingent on the mutational landscape of the tumours involved.
publishDate 2022
dc.date.none.fl_str_mv 2022
2023
2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/55662
http://dx.doi.org/10.1002/1878-0261.13295
url http://hdl.handle.net/10230/55662
http://dx.doi.org/10.1002/1878-0261.13295
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Mol Oncol. 2022 Oct;16(19):3533-53
info:eu-repo/grantAgreement/ES/2PE/RTI2018-096481-B-100
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Wiley
publisher.none.fl_str_mv Wiley
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
collection Repositorio Digital de la UPF
repository.name.fl_str_mv
repository.mail.fl_str_mv
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