Requirement for epithelial p38α in KRAS-driven lung tumor progression

Autores
Vitos Faleato, Jessica; Real Varela, Sebastián Martín; Gutiérrez Prat, Nuria; Villanueva, Alberto; Llonch llongueras, Elisabet; Drosten, Matthias; Barbacid, Mariano; Nebreda, Ángel R.
Año de publicación
2020
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Malignant transformation entails important changes in the control of cell proliferation through the rewiring of selected signaling pathways. Cancer cells then become very dependent on the proper function of those pathways, and their inhibition offers therapeutic opportunities. Here we identify the stress kinase p38α as a nononcogenic signaling molecule that enables the progression of KrasG12V-driven lung cancer. We demonstrate in vivo that, despite acting as a tumor suppressor in healthy alveolar progenitor cells, p38α contributes to the proliferation and malignization of lung cancer epithelial cells. We show that high expression levels of p38α correlate with poor survival in lung adenocarcinoma patients, and that genetic or chemical inhibition of p38α halts tumor growth in lung cancer mouse models. Moreover, we reveal a lung cancer epithelial cell-autonomous function for p38α promoting the expression of TIMP-1, which in turn stimulates cell proliferation in an autocrine manner. Altogether, our results suggest that epithelial p38α promotes KrasG12V-driven lung cancer progression via maintenance of cellular self-growth stimulatory signals.
Fil: Vitos Faleato, Jessica. Instituto de Investigación Biomédica de Barcelona.; España
Fil: Real Varela, Sebastián Martín. Instituto de Investigación Biomédica de Barcelona.; España
Fil: Gutiérrez Prat, Nuria. Instituto de Investigación Biomédica de Barcelona.; España
Fil: Villanueva, Alberto. Instituto Catalán de Oncología; España
Fil: Llonch llongueras, Elisabet. Instituto de Investigación Biomédica de Barcelona.; España
Fil: Drosten, Matthias. Centro Nacional de Investigaciones Oncologicas; España
Fil: Barbacid, Mariano. Centro Nacional de Investigaciones Oncologicas; España
Fil: Nebreda, Ángel R.. Instituto de Investigación Biomédica de Barcelona.; España
Materia
KRAS
LUNG ADENOCARCINOMA
NONONCOGENE ADDICTION
P38Α
TIMP-1
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/115093
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/115093
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Requirement for epithelial p38α in KRAS-driven lung tumor progressionVitos Faleato, JessicaReal Varela, Sebastián MartínGutiérrez Prat, NuriaVillanueva, AlbertoLlonch llongueras, ElisabetDrosten, MatthiasBarbacid, MarianoNebreda, Ángel R.KRASLUNG ADENOCARCINOMANONONCOGENE ADDICTIONP38ΑTIMP-1https://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Malignant transformation entails important changes in the control of cell proliferation through the rewiring of selected signaling pathways. Cancer cells then become very dependent on the proper function of those pathways, and their inhibition offers therapeutic opportunities. Here we identify the stress kinase p38α as a nononcogenic signaling molecule that enables the progression of KrasG12V-driven lung cancer. We demonstrate in vivo that, despite acting as a tumor suppressor in healthy alveolar progenitor cells, p38α contributes to the proliferation and malignization of lung cancer epithelial cells. We show that high expression levels of p38α correlate with poor survival in lung adenocarcinoma patients, and that genetic or chemical inhibition of p38α halts tumor growth in lung cancer mouse models. Moreover, we reveal a lung cancer epithelial cell-autonomous function for p38α promoting the expression of TIMP-1, which in turn stimulates cell proliferation in an autocrine manner. Altogether, our results suggest that epithelial p38α promotes KrasG12V-driven lung cancer progression via maintenance of cellular self-growth stimulatory signals.Fil: Vitos Faleato, Jessica. Instituto de Investigación Biomédica de Barcelona.; EspañaFil: Real Varela, Sebastián Martín. Instituto de Investigación Biomédica de Barcelona.; EspañaFil: Gutiérrez Prat, Nuria. Instituto de Investigación Biomédica de Barcelona.; EspañaFil: Villanueva, Alberto. Instituto Catalán de Oncología; EspañaFil: Llonch llongueras, Elisabet. Instituto de Investigación Biomédica de Barcelona.; EspañaFil: Drosten, Matthias. Centro Nacional de Investigaciones Oncologicas; EspañaFil: Barbacid, Mariano. Centro Nacional de Investigaciones Oncologicas; EspañaFil: Nebreda, Ángel R.. Instituto de Investigación Biomédica de Barcelona.; EspañaNational Academy of Sciences2020-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/115093Vitos Faleato, Jessica; Real Varela, Sebastián Martín; Gutiérrez Prat, Nuria; Villanueva, Alberto; Llonch llongueras, Elisabet; et al.; Requirement for epithelial p38α in KRAS-driven lung tumor progression; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 117; 5; 2-2020; 2588-25960027-8424CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://www.pnas.org/lookup/doi/10.1073/pnas.1921404117info:eu-repo/semantics/altIdentifier/doi/10.1073/pnas.1921404117info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:58:54Zoai:ri.conicet.gov.ar:11336/115093instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 09:58:54.391CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Requirement for epithelial p38α in KRAS-driven lung tumor progression
title Requirement for epithelial p38α in KRAS-driven lung tumor progression
spellingShingle Requirement for epithelial p38α in KRAS-driven lung tumor progression
Vitos Faleato, Jessica
KRAS
LUNG ADENOCARCINOMA
NONONCOGENE ADDICTION
P38Α
TIMP-1
title_short Requirement for epithelial p38α in KRAS-driven lung tumor progression
title_full Requirement for epithelial p38α in KRAS-driven lung tumor progression
title_fullStr Requirement for epithelial p38α in KRAS-driven lung tumor progression
title_full_unstemmed Requirement for epithelial p38α in KRAS-driven lung tumor progression
title_sort Requirement for epithelial p38α in KRAS-driven lung tumor progression
dc.creator.none.fl_str_mv Vitos Faleato, Jessica
Real Varela, Sebastián Martín
Gutiérrez Prat, Nuria
Villanueva, Alberto
Llonch llongueras, Elisabet
Drosten, Matthias
Barbacid, Mariano
Nebreda, Ángel R.
author Vitos Faleato, Jessica
author_facet Vitos Faleato, Jessica
Real Varela, Sebastián Martín
Gutiérrez Prat, Nuria
Villanueva, Alberto
Llonch llongueras, Elisabet
Drosten, Matthias
Barbacid, Mariano
Nebreda, Ángel R.
author_role author
author2 Real Varela, Sebastián Martín
Gutiérrez Prat, Nuria
Villanueva, Alberto
Llonch llongueras, Elisabet
Drosten, Matthias
Barbacid, Mariano
Nebreda, Ángel R.
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv KRAS
LUNG ADENOCARCINOMA
NONONCOGENE ADDICTION
P38Α
TIMP-1
topic KRAS
LUNG ADENOCARCINOMA
NONONCOGENE ADDICTION
P38Α
TIMP-1
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Malignant transformation entails important changes in the control of cell proliferation through the rewiring of selected signaling pathways. Cancer cells then become very dependent on the proper function of those pathways, and their inhibition offers therapeutic opportunities. Here we identify the stress kinase p38α as a nononcogenic signaling molecule that enables the progression of KrasG12V-driven lung cancer. We demonstrate in vivo that, despite acting as a tumor suppressor in healthy alveolar progenitor cells, p38α contributes to the proliferation and malignization of lung cancer epithelial cells. We show that high expression levels of p38α correlate with poor survival in lung adenocarcinoma patients, and that genetic or chemical inhibition of p38α halts tumor growth in lung cancer mouse models. Moreover, we reveal a lung cancer epithelial cell-autonomous function for p38α promoting the expression of TIMP-1, which in turn stimulates cell proliferation in an autocrine manner. Altogether, our results suggest that epithelial p38α promotes KrasG12V-driven lung cancer progression via maintenance of cellular self-growth stimulatory signals.
Fil: Vitos Faleato, Jessica. Instituto de Investigación Biomédica de Barcelona.; España
Fil: Real Varela, Sebastián Martín. Instituto de Investigación Biomédica de Barcelona.; España
Fil: Gutiérrez Prat, Nuria. Instituto de Investigación Biomédica de Barcelona.; España
Fil: Villanueva, Alberto. Instituto Catalán de Oncología; España
Fil: Llonch llongueras, Elisabet. Instituto de Investigación Biomédica de Barcelona.; España
Fil: Drosten, Matthias. Centro Nacional de Investigaciones Oncologicas; España
Fil: Barbacid, Mariano. Centro Nacional de Investigaciones Oncologicas; España
Fil: Nebreda, Ángel R.. Instituto de Investigación Biomédica de Barcelona.; España
description Malignant transformation entails important changes in the control of cell proliferation through the rewiring of selected signaling pathways. Cancer cells then become very dependent on the proper function of those pathways, and their inhibition offers therapeutic opportunities. Here we identify the stress kinase p38α as a nononcogenic signaling molecule that enables the progression of KrasG12V-driven lung cancer. We demonstrate in vivo that, despite acting as a tumor suppressor in healthy alveolar progenitor cells, p38α contributes to the proliferation and malignization of lung cancer epithelial cells. We show that high expression levels of p38α correlate with poor survival in lung adenocarcinoma patients, and that genetic or chemical inhibition of p38α halts tumor growth in lung cancer mouse models. Moreover, we reveal a lung cancer epithelial cell-autonomous function for p38α promoting the expression of TIMP-1, which in turn stimulates cell proliferation in an autocrine manner. Altogether, our results suggest that epithelial p38α promotes KrasG12V-driven lung cancer progression via maintenance of cellular self-growth stimulatory signals.
publishDate 2020
dc.date.none.fl_str_mv 2020-02
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/115093
Vitos Faleato, Jessica; Real Varela, Sebastián Martín; Gutiérrez Prat, Nuria; Villanueva, Alberto; Llonch llongueras, Elisabet; et al.; Requirement for epithelial p38α in KRAS-driven lung tumor progression; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 117; 5; 2-2020; 2588-2596
0027-8424
CONICET Digital
CONICET
url http://hdl.handle.net/11336/115093
identifier_str_mv Vitos Faleato, Jessica; Real Varela, Sebastián Martín; Gutiérrez Prat, Nuria; Villanueva, Alberto; Llonch llongueras, Elisabet; et al.; Requirement for epithelial p38α in KRAS-driven lung tumor progression; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 117; 5; 2-2020; 2588-2596
0027-8424
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.pnas.org/lookup/doi/10.1073/pnas.1921404117
info:eu-repo/semantics/altIdentifier/doi/10.1073/pnas.1921404117
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv National Academy of Sciences
publisher.none.fl_str_mv National Academy of Sciences
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1842269548598788096
score 13.13397

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