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

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• dc.contributor.author Robles-Valero, Javier
• dc.contributor.author Fernández-Nevado, Lucía
• dc.contributor.author Cuadrado, Myriam
• dc.contributor.author Lorenzo-Martín, L. Francisco
• dc.contributor.author Fernández-Pisonero, Isabel
• dc.contributor.author Abad, Antonio
• dc.contributor.author Redín, Esther
• dc.contributor.author Montuenga, Luis
• dc.contributor.author Martín-Zanca, Dionisio
• dc.contributor.author Bigas Salvans, Anna
• dc.contributor.author Mallo, Moises
• dc.contributor.author Dosil, Mercedes
• dc.contributor.author Bustelo, Xose R.
• dc.date.accessioned 2023-02-07T13:07:25Z
• dc.date.available 2023-02-07T13:07:25Z
• dc.date.issued 2022
• dc.description.abstract 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.
• dc.description.sponsorship 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.
• dc.format.mimetype application/pdf
• dc.identifier.citation Robles-Valero J, Fernández-Nevado L, Cuadrado M, Lorenzo-Martín LF, Fernández-Pisonero I, Abad A, Redín E, Montuenga L, Martín-Zanca D, Bigas A, Mallo M, Dosil M, Bustelo XR. Characterization of the spectrum of trivalent VAV1-mutation-driven tumours using a gene-edited mouse model. Mol Oncol. 2022 Oct;16(19):3533-53. DOI: 10.1002/1878-0261.13295
• dc.identifier.doi http://dx.doi.org/10.1002/1878-0261.13295
• dc.identifier.issn 1574-7891
• dc.identifier.uri http://hdl.handle.net/10230/55662
• dc.language.iso eng
• dc.publisher Wiley
• dc.relation.ispartof Mol Oncol. 2022 Oct;16(19):3533-53
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-096481-B-100
• dc.rights © 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.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword RAC1
• dc.subject.keyword TP53
• dc.subject.keyword Angioimmunoblastic T cell lymphoma
• dc.subject.keyword Follicular helper T cells
• dc.subject.keyword Nonsmall-cell lung cancer
• dc.subject.keyword Peripheral T cell lymphoma
• dc.title Characterization of the spectrum of trivalent VAV1-mutation-driven tumours using a gene-edited mouse model
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion