VAV2 orchestrates the interplay between regenerative proliferation and ribogenesis in both keratinocytes and oral squamous cell carcinoma

VAV2 is an activator of RHO GTPases that promotes and maintains regenerative proliferation-like states in normal keratinocytes and oral squamous cell carcinoma (OSCC) cells. Here, we demonstrate that VAV2 also regulates ribosome biogenesis in those cells, a program associated with poor prognosis of...

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Autores: Fernández-Parejo, Natalia, Lorenzo-Martín, L. Francisco, García-Pedrero, Juana María, Rodrigo, Juan P., Dosil, Mercedes, Bustelo, Xosé R.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/365024
Acceso en línea:http://hdl.handle.net/10261/365024
Access Level:acceso abierto
Palabra clave:Guanosine nucleotide exchange factors
RHO GTPases
RAC1
RHOA
PAK1
ROCK
YAP/TAZ
Ribosomes
RNA polymerase I
Patient-derived cells
Patient prognosis
Oncogenic signaling
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oai_identifier_str oai:digital.csic.es:10261/365024
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv VAV2 orchestrates the interplay between regenerative proliferation and ribogenesis in both keratinocytes and oral squamous cell carcinoma
title VAV2 orchestrates the interplay between regenerative proliferation and ribogenesis in both keratinocytes and oral squamous cell carcinoma
spellingShingle VAV2 orchestrates the interplay between regenerative proliferation and ribogenesis in both keratinocytes and oral squamous cell carcinoma
Fernández-Parejo, Natalia
Guanosine nucleotide exchange factors
RHO GTPases
RAC1
RHOA
PAK1
ROCK
YAP/TAZ
Ribosomes
RNA polymerase I
Patient-derived cells
Patient prognosis
Oncogenic signaling
title_short VAV2 orchestrates the interplay between regenerative proliferation and ribogenesis in both keratinocytes and oral squamous cell carcinoma
title_full VAV2 orchestrates the interplay between regenerative proliferation and ribogenesis in both keratinocytes and oral squamous cell carcinoma
title_fullStr VAV2 orchestrates the interplay between regenerative proliferation and ribogenesis in both keratinocytes and oral squamous cell carcinoma
title_full_unstemmed VAV2 orchestrates the interplay between regenerative proliferation and ribogenesis in both keratinocytes and oral squamous cell carcinoma
title_sort VAV2 orchestrates the interplay between regenerative proliferation and ribogenesis in both keratinocytes and oral squamous cell carcinoma
dc.creator.none.fl_str_mv Fernández-Parejo, Natalia
Lorenzo-Martín, L. Francisco
García-Pedrero, Juana María
Rodrigo, Juan P.
Dosil, Mercedes
Bustelo, Xosé R.
author Fernández-Parejo, Natalia
author_facet Fernández-Parejo, Natalia
Lorenzo-Martín, L. Francisco
García-Pedrero, Juana María
Rodrigo, Juan P.
Dosil, Mercedes
Bustelo, Xosé R.
author_role author
author2 Lorenzo-Martín, L. Francisco
García-Pedrero, Juana María
Rodrigo, Juan P.
Dosil, Mercedes
Bustelo, Xosé R.
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Worldwide Cancer Research
Ministerio de Ciencia, Innovación y Universidades (España)
Agencia Estatal de Investigación (España)
European Commission
La Caixa
Fundación Científica Asociación Española Contra el Cáncer
Ministerio de Educación, Cultura y Deporte (España)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Guanosine nucleotide exchange factors
RHO GTPases
RAC1
RHOA
PAK1
ROCK
YAP/TAZ
Ribosomes
RNA polymerase I
Patient-derived cells
Patient prognosis
Oncogenic signaling
topic Guanosine nucleotide exchange factors
RHO GTPases
RAC1
RHOA
PAK1
ROCK
YAP/TAZ
Ribosomes
RNA polymerase I
Patient-derived cells
Patient prognosis
Oncogenic signaling
description VAV2 is an activator of RHO GTPases that promotes and maintains regenerative proliferation-like states in normal keratinocytes and oral squamous cell carcinoma (OSCC) cells. Here, we demonstrate that VAV2 also regulates ribosome biogenesis in those cells, a program associated with poor prognosis of human papilloma virus-negative (HPV−) OSCC patients. Mechanistically, VAV2 regulates this process in a catalysis-dependent manner using a conserved pathway comprising the RAC1 and RHOA GTPases, the PAK and ROCK family kinases, and the c-MYC and YAP/TAZ transcription factors. This pathway directly promotes RNA polymerase I activity and synthesis of 47S pre-rRNA precursors. This process is further consolidated by the upregulation of ribosome biogenesis factors and the acquisition of the YAP/TAZ-dependent undifferentiated cell state. Finally, we show that RNA polymerase I is a therapeutic Achilles’ heel for both keratinocytes and OSCC patient-derived cells endowed with high VAV2 catalytic activity. Collectively, these findings highlight the therapeutic potential of modulating VAV2 and the ribosome biogenesis pathways in both preneoplastic and late progression stages of OSCC.
publishDate 2024
dc.date.none.fl_str_mv 2024
2024
2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/365024
url http://hdl.handle.net/10261/365024
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2021-122666OB-I00
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-118378GB-I00
Fernández-Parejo, Natalia; Lorenzo-Martín, L. Francisco; García-Pedrero, Juana María; Rodrigo, Juan P.; Dosil, Mercedes; Bustelo, Xosé R.; 2024; Supplementary Information for VAV2 orchestrates the interplay between regenerative proliferation and ribogenesis in both keratinocytes and oral squamous cell carcinoma [Dataset]; Springer Nature; https://doi.org/10.1038/s41598-024-54808-0
https://doi.org/10.1038/s41598-024-54808-0
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Springer Nature
publisher.none.fl_str_mv Springer Nature
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling VAV2 orchestrates the interplay between regenerative proliferation and ribogenesis in both keratinocytes and oral squamous cell carcinomaFernández-Parejo, NataliaLorenzo-Martín, L. FranciscoGarcía-Pedrero, Juana MaríaRodrigo, Juan P.Dosil, MercedesBustelo, Xosé R.Guanosine nucleotide exchange factorsRHO GTPasesRAC1RHOAPAK1ROCKYAP/TAZRibosomesRNA polymerase IPatient-derived cellsPatient prognosisOncogenic signalingVAV2 is an activator of RHO GTPases that promotes and maintains regenerative proliferation-like states in normal keratinocytes and oral squamous cell carcinoma (OSCC) cells. Here, we demonstrate that VAV2 also regulates ribosome biogenesis in those cells, a program associated with poor prognosis of human papilloma virus-negative (HPV−) OSCC patients. Mechanistically, VAV2 regulates this process in a catalysis-dependent manner using a conserved pathway comprising the RAC1 and RHOA GTPases, the PAK and ROCK family kinases, and the c-MYC and YAP/TAZ transcription factors. This pathway directly promotes RNA polymerase I activity and synthesis of 47S pre-rRNA precursors. This process is further consolidated by the upregulation of ribosome biogenesis factors and the acquisition of the YAP/TAZ-dependent undifferentiated cell state. Finally, we show that RNA polymerase I is a therapeutic Achilles’ heel for both keratinocytes and OSCC patient-derived cells endowed with high VAV2 catalytic activity. Collectively, these findings highlight the therapeutic potential of modulating VAV2 and the ribosome biogenesis pathways in both preneoplastic and late progression stages of OSCC.We thank A. Abad and C. García-Macías for lab and pathology work, respectively. X.R.B.’s project leading to these results has received funding from Worldwide Cancer Research (14-1248), the Castilla-León government (CSI145P20, CLC-2017-01), grants cofounded by MCIN/AEI/https://doi.org/10.13039/501100011033/ plus the European Research Development Fund “A way of making Europe” of the European Union (PID2021-122666OB-I00), “la Caixa” Banking Foundation (HR20-00164), and the Programa Excelencia of the Fundación Científica AECC 2022 (EPAEC222641CICS). M.D.’s work has been supported by a grant cofounded by MCIN/AEI/https://doi.org/10.13039/501100011033/ plus the European Research Development Fund “A way of making Europe” of the European Union (PID2020-118378GB-I00). The authors’ institution was supported by the Programas de Apoyo a Planes Estratégicos de Investigación de Estructuras de Investigación de Excelencia of the Castilla-León government (CLC-2017-01 and CL-EI-2021-02) that were both cofounded by the European Research Development Fund. N.P. contract has been mostly supported by funding from the Spanish Ministry of Universities (FPU17/03912) and, subsequently, by the HR20-00164 grant (see above). L.F.L.-M. contract has been mostly supported by funding from the Spanish Ministry of Education, Culture and Sports (FPU13/02923) and, subsequently, by the CLC-2017-01 grant.Peer reviewedSpringer NatureWorldwide Cancer ResearchMinisterio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)European CommissionLa CaixaFundación Científica Asociación Española Contra el CáncerMinisterio de Educación, Cultura y Deporte (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202420242024info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/365024reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2021-122666OB-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-118378GB-I00Fernández-Parejo, Natalia; Lorenzo-Martín, L. Francisco; García-Pedrero, Juana María; Rodrigo, Juan P.; Dosil, Mercedes; Bustelo, Xosé R.; 2024; Supplementary Information for VAV2 orchestrates the interplay between regenerative proliferation and ribogenesis in both keratinocytes and oral squamous cell carcinoma [Dataset]; Springer Nature; https://doi.org/10.1038/s41598-024-54808-0https://doi.org/10.1038/s41598-024-54808-0Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3650242026-05-22T06:33:51Z
score 15,198674

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