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ACSL3-PAI-1 signaling axis mediates tumor-stroma cross-talk promoting pancreatic cancer progression.
Rossi Sebastiano, Matteo; Pozzato, Chiara; Saliakoura, Maria; Yang, Zhang; Peng, Ren-Wang; Galiè, Mirco; Oberson, Kevin; Simon, Hans-Uwe; Karamitopoulou, Evanthia; Konstantinidou, Georgia.
Afiliación
  • Rossi Sebastiano M; Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland.
  • Pozzato C; Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland.
  • Saliakoura M; Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland.
  • Yang Z; Division of General Thoracic Surgery, Inselspital, Bern University Hospital, 3008 Bern, Switzerland.
  • Peng RW; Division of General Thoracic Surgery, Inselspital, Bern University Hospital, 3008 Bern, Switzerland.
  • Galiè M; Department of Neuroscience, Biomedicine and Movement, University of Verona, 37134 Verona, Italy.
  • Oberson K; Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland.
  • Simon HU; Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland.
  • Karamitopoulou E; Department of Clinical Immunology and Allergology, Sechenov University, Moscow, Russia.
  • Konstantinidou G; Institute of Pathology, University of Bern, 3008 Bern, Switzerland.
Sci Adv ; 6(44)2020 10.
Article en En | MEDLINE | ID: mdl-33127675
Pancreatic ductal adenocarcinoma (PDAC) is characterized by marked fibrosis and low immunogenicity, features that are linked to treatment resistance and poor clinical outcomes. Therefore, understanding how PDAC regulates the desmoplastic and immune stromal components is of great clinical importance. We found that acyl-CoA synthetase long-chain 3 (ACSL3) is up-regulated in PDAC and correlates with increased fibrosis. Our in vivo results show that Acsl3 knockout hinders PDAC progression, markedly reduces tumor fibrosis and tumor-infiltrating immunosuppressive cells, and increases cytotoxic T cell infiltration. This effect is, at least in part, due to decreased plasminogen activator inhibitor-1 (PAI-1) secretion from tumor cells. Accordingly, PAI-1 expression in PDAC positively correlates with markers of fibrosis and immunosuppression and predicts poor patient survival. We found that PAI-1 pharmacological inhibition strongly enhances chemo- and immunotherapeutic response against PDAC, increasing survival of mice. Thus, our results unveil ACSL3-PAI-1 signaling as a requirement for PDAC progression with druggable attributes.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Coenzima A Ligasas / Carcinoma Ductal Pancreático Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Sci Adv Año: 2020 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Coenzima A Ligasas / Carcinoma Ductal Pancreático Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Sci Adv Año: 2020 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Estados Unidos