TGF-β2 dictates disseminated tumour cell fate in target organs through TGF-β-RIII and p38α/β signalling

Autores
Bragado, Paloma; Estrada, Yeriel; Parikh, Falguni; Krause, Sarah; Capobianco, Carla Sabrina; Farina, Hernán Gabriel; Schewe, Denis M.; Aguirre Ghiso, Julio A.
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
In patients, non-proliferative disseminated tumour cells (DTCs) can persist in the bone marrow (BM) while other organs (such as lung) present growing metastasis. This suggested that the BM might be a metastasis ‘restrictive soil’ by encoding dormancy-inducing cues in DTCs. Here we show in a head and neck squamous cell carcinoma (HNSCC) model that strong and specific transforming growth factor-β2 (TGF-β2) signalling in the BM activates the MAPK p38α/β, inducing an (ERK/p38)low signalling ratio. This results in induction of DEC2/SHARP1 and p27, downregulation of cyclin-dependent kinase 4 (CDK4) and dormancy of malignant DTCs. TGF-β2-induced dormancy required TGF-β receptor-I (TGF-β-RI), TGF-β-RIII and SMAD1/5 activation to induce p27. In lungs, a metastasis ‘permissive soil’ with low TGF-β2 levels, DTC dormancy was short-lived and followed by metastatic growth. Importantly, systemic inhibition of TGF-β-RI or p38α/β activities awakened dormant DTCs, fuelling multi-organ metastasis. Our work reveals a ‘seed and soil’ mechanism where TGF-β2 and TGF-β-RIII signalling through p38α/β regulates DTC dormancy and defines restrictive (BM) and permissive (lung) microenvironments for HNSCC metastasis.
Fil: Bragado, Paloma. Mount Sinai School of Medicine. Tisch Cancer Institute; Estados Unidos
Fil: Estrada, Yeriel. Mount Sinai School of Medicine. Tisch Cancer Institute; Estados Unidos
Fil: Parikh, Falguni. Mount Sinai School of Medicine. Tisch Cancer Institute; Estados Unidos
Fil: Krause, Sarah. University Hospital of Schleswig-Holstein; Alemania
Fil: Capobianco, Carla Sabrina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Farina, Hernán Gabriel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Schewe, Denis M.. Mount Sinai School of Medicine. Tisch Cancer Institute; Estados Unidos
Fil: Aguirre Ghiso, Julio A.. Mount Sinai School of Medicine. Tisch Cancer Institute; Estados Unidos
Materia
p38 MAP KINASE
DORMANCY
CANCER
TGF
DTC
Quiescence
Target organ
Seed and soil
Metastasis
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:11336/24959
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/24959
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling TGF-β2 dictates disseminated tumour cell fate in target organs through TGF-β-RIII and p38α/β signallingBragado, PalomaEstrada, YerielParikh, FalguniKrause, SarahCapobianco, Carla SabrinaFarina, Hernán GabrielSchewe, Denis M.Aguirre Ghiso, Julio A.p38 MAP KINASEDORMANCYCANCERTGFDTCQuiescenceTarget organSeed and soilMetastasishttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1In patients, non-proliferative disseminated tumour cells (DTCs) can persist in the bone marrow (BM) while other organs (such as lung) present growing metastasis. This suggested that the BM might be a metastasis ‘restrictive soil’ by encoding dormancy-inducing cues in DTCs. Here we show in a head and neck squamous cell carcinoma (HNSCC) model that strong and specific transforming growth factor-β2 (TGF-β2) signalling in the BM activates the MAPK p38α/β, inducing an (ERK/p38)low signalling ratio. This results in induction of DEC2/SHARP1 and p27, downregulation of cyclin-dependent kinase 4 (CDK4) and dormancy of malignant DTCs. TGF-β2-induced dormancy required TGF-β receptor-I (TGF-β-RI), TGF-β-RIII and SMAD1/5 activation to induce p27. In lungs, a metastasis ‘permissive soil’ with low TGF-β2 levels, DTC dormancy was short-lived and followed by metastatic growth. Importantly, systemic inhibition of TGF-β-RI or p38α/β activities awakened dormant DTCs, fuelling multi-organ metastasis. Our work reveals a ‘seed and soil’ mechanism where TGF-β2 and TGF-β-RIII signalling through p38α/β regulates DTC dormancy and defines restrictive (BM) and permissive (lung) microenvironments for HNSCC metastasis.Fil: Bragado, Paloma. Mount Sinai School of Medicine. Tisch Cancer Institute; Estados UnidosFil: Estrada, Yeriel. Mount Sinai School of Medicine. Tisch Cancer Institute; Estados UnidosFil: Parikh, Falguni. Mount Sinai School of Medicine. Tisch Cancer Institute; Estados UnidosFil: Krause, Sarah. University Hospital of Schleswig-Holstein; AlemaniaFil: Capobianco, Carla Sabrina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Farina, Hernán Gabriel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Schewe, Denis M.. Mount Sinai School of Medicine. Tisch Cancer Institute; Estados UnidosFil: Aguirre Ghiso, Julio A.. Mount Sinai School of Medicine. Tisch Cancer Institute; Estados UnidosNature Publishing Group2013-09info: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/11336/24959Bragado, Paloma; Estrada, Yeriel; Parikh, Falguni; Krause, Sarah; Capobianco, Carla Sabrina; et al.; TGF-β2 dictates disseminated tumour cell fate in target organs through TGF-β-RIII and p38α/β signalling; Nature Publishing Group; Nature Cell Biology; 15; 11; 9-2013; 1351-13611465-73921476-4679CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1038/ncb2861info:eu-repo/semantics/altIdentifier/url/http://www.nature.com/ncb/journal/v15/n11/full/ncb2861.htmlinfo:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4006312/info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-11-12T09:35:41Zoai:ri.conicet.gov.ar:11336/24959instacron: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:34982025-11-12 09:35:41.698CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv TGF-β2 dictates disseminated tumour cell fate in target organs through TGF-β-RIII and p38α/β signalling
title TGF-β2 dictates disseminated tumour cell fate in target organs through TGF-β-RIII and p38α/β signalling
spellingShingle TGF-β2 dictates disseminated tumour cell fate in target organs through TGF-β-RIII and p38α/β signalling
Bragado, Paloma
p38 MAP KINASE
DORMANCY
CANCER
TGF
DTC
Quiescence
Target organ
Seed and soil
Metastasis
title_short TGF-β2 dictates disseminated tumour cell fate in target organs through TGF-β-RIII and p38α/β signalling
title_full TGF-β2 dictates disseminated tumour cell fate in target organs through TGF-β-RIII and p38α/β signalling
title_fullStr TGF-β2 dictates disseminated tumour cell fate in target organs through TGF-β-RIII and p38α/β signalling
title_full_unstemmed TGF-β2 dictates disseminated tumour cell fate in target organs through TGF-β-RIII and p38α/β signalling
title_sort TGF-β2 dictates disseminated tumour cell fate in target organs through TGF-β-RIII and p38α/β signalling
dc.creator.none.fl_str_mv Bragado, Paloma
Estrada, Yeriel
Parikh, Falguni
Krause, Sarah
Capobianco, Carla Sabrina
Farina, Hernán Gabriel
Schewe, Denis M.
Aguirre Ghiso, Julio A.
author Bragado, Paloma
author_facet Bragado, Paloma
Estrada, Yeriel
Parikh, Falguni
Krause, Sarah
Capobianco, Carla Sabrina
Farina, Hernán Gabriel
Schewe, Denis M.
Aguirre Ghiso, Julio A.
author_role author
author2 Estrada, Yeriel
Parikh, Falguni
Krause, Sarah
Capobianco, Carla Sabrina
Farina, Hernán Gabriel
Schewe, Denis M.
Aguirre Ghiso, Julio A.
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv p38 MAP KINASE
DORMANCY
CANCER
TGF
DTC
Quiescence
Target organ
Seed and soil
Metastasis
topic p38 MAP KINASE
DORMANCY
CANCER
TGF
DTC
Quiescence
Target organ
Seed and soil
Metastasis
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv In patients, non-proliferative disseminated tumour cells (DTCs) can persist in the bone marrow (BM) while other organs (such as lung) present growing metastasis. This suggested that the BM might be a metastasis ‘restrictive soil’ by encoding dormancy-inducing cues in DTCs. Here we show in a head and neck squamous cell carcinoma (HNSCC) model that strong and specific transforming growth factor-β2 (TGF-β2) signalling in the BM activates the MAPK p38α/β, inducing an (ERK/p38)low signalling ratio. This results in induction of DEC2/SHARP1 and p27, downregulation of cyclin-dependent kinase 4 (CDK4) and dormancy of malignant DTCs. TGF-β2-induced dormancy required TGF-β receptor-I (TGF-β-RI), TGF-β-RIII and SMAD1/5 activation to induce p27. In lungs, a metastasis ‘permissive soil’ with low TGF-β2 levels, DTC dormancy was short-lived and followed by metastatic growth. Importantly, systemic inhibition of TGF-β-RI or p38α/β activities awakened dormant DTCs, fuelling multi-organ metastasis. Our work reveals a ‘seed and soil’ mechanism where TGF-β2 and TGF-β-RIII signalling through p38α/β regulates DTC dormancy and defines restrictive (BM) and permissive (lung) microenvironments for HNSCC metastasis.
Fil: Bragado, Paloma. Mount Sinai School of Medicine. Tisch Cancer Institute; Estados Unidos
Fil: Estrada, Yeriel. Mount Sinai School of Medicine. Tisch Cancer Institute; Estados Unidos
Fil: Parikh, Falguni. Mount Sinai School of Medicine. Tisch Cancer Institute; Estados Unidos
Fil: Krause, Sarah. University Hospital of Schleswig-Holstein; Alemania
Fil: Capobianco, Carla Sabrina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Farina, Hernán Gabriel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Schewe, Denis M.. Mount Sinai School of Medicine. Tisch Cancer Institute; Estados Unidos
Fil: Aguirre Ghiso, Julio A.. Mount Sinai School of Medicine. Tisch Cancer Institute; Estados Unidos
description In patients, non-proliferative disseminated tumour cells (DTCs) can persist in the bone marrow (BM) while other organs (such as lung) present growing metastasis. This suggested that the BM might be a metastasis ‘restrictive soil’ by encoding dormancy-inducing cues in DTCs. Here we show in a head and neck squamous cell carcinoma (HNSCC) model that strong and specific transforming growth factor-β2 (TGF-β2) signalling in the BM activates the MAPK p38α/β, inducing an (ERK/p38)low signalling ratio. This results in induction of DEC2/SHARP1 and p27, downregulation of cyclin-dependent kinase 4 (CDK4) and dormancy of malignant DTCs. TGF-β2-induced dormancy required TGF-β receptor-I (TGF-β-RI), TGF-β-RIII and SMAD1/5 activation to induce p27. In lungs, a metastasis ‘permissive soil’ with low TGF-β2 levels, DTC dormancy was short-lived and followed by metastatic growth. Importantly, systemic inhibition of TGF-β-RI or p38α/β activities awakened dormant DTCs, fuelling multi-organ metastasis. Our work reveals a ‘seed and soil’ mechanism where TGF-β2 and TGF-β-RIII signalling through p38α/β regulates DTC dormancy and defines restrictive (BM) and permissive (lung) microenvironments for HNSCC metastasis.
publishDate 2013
dc.date.none.fl_str_mv 2013-09
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/11336/24959
Bragado, Paloma; Estrada, Yeriel; Parikh, Falguni; Krause, Sarah; Capobianco, Carla Sabrina; et al.; TGF-β2 dictates disseminated tumour cell fate in target organs through TGF-β-RIII and p38α/β signalling; Nature Publishing Group; Nature Cell Biology; 15; 11; 9-2013; 1351-1361
1465-7392
1476-4679
CONICET Digital
CONICET
url http://hdl.handle.net/11336/24959
identifier_str_mv Bragado, Paloma; Estrada, Yeriel; Parikh, Falguni; Krause, Sarah; Capobianco, Carla Sabrina; et al.; TGF-β2 dictates disseminated tumour cell fate in target organs through TGF-β-RIII and p38α/β signalling; Nature Publishing Group; Nature Cell Biology; 15; 11; 9-2013; 1351-1361
1465-7392
1476-4679
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1038/ncb2861
info:eu-repo/semantics/altIdentifier/url/http://www.nature.com/ncb/journal/v15/n11/full/ncb2861.html
info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4006312/
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 Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
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
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score 13.25334

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