RESUMO
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a high degree of inflammation and profound immune suppression. Here we identify Yes-associated protein (Yap) as a critical regulator of the immunosuppressive microenvironment in both mouse and human PDAC. Within Kras:p53 mutant pancreatic ductal cells, Yap drives the expression and secretion of multiple cytokines/chemokines, which in turn promote the differentiation and accumulation of myeloid-derived suppressor cells (MDSCs) both in vitro and in vivo. Pancreas-specific knockout of Yap or antibody-mediated depletion of MDSCs promoted macrophage reprogramming, reactivation of T cells, apoptosis of Kras mutant neoplastic ductal cells and pancreatic regeneration after acute pancreatitis. In primary human PDAC, YAP expression levels strongly correlate with an MDSC gene signature, and high expression of YAP or MDSC-related genes predicts decreased survival in PDAC patients. These results reveal multifaceted roles of YAP in PDAC pathogenesis and underscore its promise as a therapeutic target for this deadly disease.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Adenocarcinoma/imunologia , Carcinoma Ductal Pancreático/imunologia , Inflamação/imunologia , Neoplasias Pancreáticas/imunologia , Pancreatite/imunologia , Fosfoproteínas/metabolismo , Fosfoproteínas/fisiologia , Doença Aguda , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Apoptose , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Proteínas de Ciclo Celular , Diferenciação Celular , Proliferação de Células , Citocinas/metabolismo , Humanos , Inflamação/metabolismo , Inflamação/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Mutação/genética , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Células Supressoras Mieloides/patologia , Estadiamento de Neoplasias , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Pancreatite/metabolismo , Pancreatite/patologia , Fosfoproteínas/genética , Prognóstico , Proteínas Proto-Oncogênicas p21(ras)/genética , Taxa de Sobrevida , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Fatores de Transcrição , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas de Sinalização YAP , Neoplasias PancreáticasRESUMO
Mounting evidence links deregulated protein synthesis to tumorigenesis via the translation initiation factor complex eIF4F. Components of this complex are often overexpressed in a large number of cancers and promote malignant transformation in experimental systems. mTOR affects the activity of the eIF4F complex by phosphorylating repressors of the eIF4F complex, the eIF4E binding proteins. The immunosuppressant rapamycin specifically inhibits mTOR activity and retards cancer growth. Importantly, mutations in upstream negative regulators of mTOR cause hamartomas, haemangiomas, and cancers that are sensitive to rapamycin treatment. Such mutations lead to increased eIF4F formation and consequently to enhanced translation initiation and cell growth. Thus, inhibition of translation initiation through targeting the mTOR-signalling pathway is emerging as a promising therapeutic option.
RESUMO
Mounting evidence links deregulated protein synthesis to tumorigenesis via the translation initiation factor complex eIF4F. Components of this complex are often overexpressed in a large number of cancers and promote malignant transformation in experimental systems. mTOR affects the activity of the eIF4F complex by phosphorylating repressors of the eIF4F complex, the eIF4E binding proteins. The immunosuppressant rapamycin specifically inhibits mTOR activity and retards cancer growth. Importantly, mutations in upstream negative regulators of mTOR cause hamartomas, haemangiomas, and cancers that are sensitive to rapamycin treatment. Such mutations lead to increased eIF4F formation and consequently to enhanced translation initiation and cell growth. Thus, inhibition of translation initiation through targeting the mTOR-signalling pathway is emerging as a promising therapeutic option.