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GPER is a mechanoregulator of pancreatic stellate cells and the tumor microenvironment.
Cortes, Ernesto; Sarper, Muge; Robinson, Benjamin; Lachowski, Dariusz; Chronopoulos, Antonios; Thorpe, Stephen D; Lee, David A; Del Río Hernández, Armando E.
Afiliação
  • Cortes E; Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London, UK.
  • Sarper M; Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London, UK.
  • Robinson B; Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London, UK.
  • Lachowski D; Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London, UK.
  • Chronopoulos A; Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London, UK.
  • Thorpe SD; Institute of Bioengineering, School of Engineering and Materials Science, Queen Mary University of London, London, UK s.thorpe@qmul.ac.uk a.del-rio-hernandez@imperial.ac.uk.
  • Lee DA; Institute of Bioengineering, School of Engineering and Materials Science, Queen Mary University of London, London, UK.
  • Del Río Hernández AE; Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London, UK s.thorpe@qmul.ac.uk a.del-rio-hernandez@imperial.ac.uk.
EMBO Rep ; 20(1)2019 01.
Article em En | MEDLINE | ID: mdl-30538117
ABSTRACT
The mechanical properties of the tumor microenvironment are emerging as attractive targets for the development of therapies. Tamoxifen, an agonist of the G protein-coupled estrogen receptor (GPER), is widely used to treat estrogen-positive breast cancer. Here, we show that tamoxifen mechanically reprograms the tumor microenvironment through a newly identified GPER-mediated mechanism. Tamoxifen inhibits the myofibroblastic differentiation of pancreatic stellate cells (PSCs) in the tumor microenvironment of pancreatic cancer in an acto-myosin-dependent manner via RhoA-mediated contractility, YAP deactivation, and GPER signaling. This hampers the ability of PSCs to remodel the extracellular matrix and to promote cancer cell invasion. Tamoxifen also reduces the recruitment and polarization to the M2 phenotype of tumor-associated macrophages. Our results highlight GPER as a mechanical regulator of the tumor microenvironment that targets the three hallmarks of pancreatic cancer desmoplasia, inflammation, and immune suppression. The well-established safety of tamoxifen in clinics may offer the possibility to redirect the singular focus of tamoxifen on the cancer cells to the greater tumor microenvironment and lead a new strategy of drug repurposing.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Tamoxifeno / Receptores de Estrogênio / Receptores Acoplados a Proteínas G / Células Estreladas do Pâncreas Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: EMBO Rep Assunto da revista: BIOLOGIA MOLECULAR Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Reino Unido

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Tamoxifeno / Receptores de Estrogênio / Receptores Acoplados a Proteínas G / Células Estreladas do Pâncreas Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: EMBO Rep Assunto da revista: BIOLOGIA MOLECULAR Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Reino Unido