학술논문
Pharmacologic Normalization of Pancreatic Cancer-Associated Fibroblast Secretome Impairs Prometastatic Cross-Talk With Macrophages.
Document Type
Academic Journal
Author
Samain R; Centre de Recherches en Cancérologie de Toulouse (CRCT), Université de Toulouse, INSERM Unité Mixte de Recherche UMR-1037, CNRS Equipe de Recherche Labellisée ERL5294, Equipe de Recherche Labellisée 'Ligue Contre le Cancer' & 'LabEx Toucan', Toulouse, France.; Brunel A; Centre de Recherches en Cancérologie de Toulouse (CRCT), Université de Toulouse, INSERM Unité Mixte de Recherche UMR-1037, CNRS Equipe de Recherche Labellisée ERL5294, Equipe de Recherche Labellisée 'Ligue Contre le Cancer' & 'LabEx Toucan', Toulouse, France.; Douché T; Centre de Recherches en Cancérologie de Toulouse (CRCT), Université de Toulouse, INSERM Unité Mixte de Recherche UMR-1037, CNRS Equipe de Recherche Labellisée ERL5294, Equipe de Recherche Labellisée 'Ligue Contre le Cancer' & 'LabEx Toucan', Toulouse, France.; Fanjul M; Centre de Recherches en Cancérologie de Toulouse (CRCT), Université de Toulouse, INSERM Unité Mixte de Recherche UMR-1037, CNRS Equipe de Recherche Labellisée ERL5294, Equipe de Recherche Labellisée 'Ligue Contre le Cancer' & 'LabEx Toucan', Toulouse, France.; Cassant-Sourdy S; Centre de Recherches en Cancérologie de Toulouse (CRCT), Université de Toulouse, INSERM Unité Mixte de Recherche UMR-1037, CNRS Equipe de Recherche Labellisée ERL5294, Equipe de Recherche Labellisée 'Ligue Contre le Cancer' & 'LabEx Toucan', Toulouse, France.; Rochotte J; Centre de Recherches en Cancérologie de Toulouse (CRCT), Université de Toulouse, INSERM Unité Mixte de Recherche UMR-1037, CNRS Equipe de Recherche Labellisée ERL5294, Equipe de Recherche Labellisée 'Ligue Contre le Cancer' & 'LabEx Toucan', Toulouse, France.; Cros J; Department of Pathology, Beaujon-Bichat University Hospital-Paris Diderot University, Clichy, France.; Neuzillet C; Medical Oncology Department, Curie Institute, Versailles Saint-Quentin University, Saint Cloud, France.; Raffenne J; Centre de Recherches en Cancérologie de Toulouse (CRCT), Université de Toulouse, INSERM Unité Mixte de Recherche UMR-1037, CNRS Equipe de Recherche Labellisée ERL5294, Equipe de Recherche Labellisée 'Ligue Contre le Cancer' & 'LabEx Toucan', Toulouse, France.; Duluc C; Centre de Recherches en Cancérologie de Toulouse (CRCT), Université de Toulouse, INSERM Unité Mixte de Recherche UMR-1037, CNRS Equipe de Recherche Labellisée ERL5294, Equipe de Recherche Labellisée 'Ligue Contre le Cancer' & 'LabEx Toucan', Toulouse, France.; Perraud A; Equipe d'Accueil EA 3842 Laboratory, Medicine and Pharmacy Faculties, University of Limoges, Limoges, France.; Nigri J; INSERM U1068/UMR 7258 CNRS, Cancer Research Center of Marseille, Marseille, France.; Gigoux V; Centre de Recherches en Cancérologie de Toulouse (CRCT), Université de Toulouse, INSERM Unité Mixte de Recherche UMR-1037, CNRS Equipe de Recherche Labellisée ERL5294, Equipe de Recherche Labellisée 'Ligue Contre le Cancer' & 'LabEx Toucan', Toulouse, France.; Bieche I; Department of Genetics, Institut Curie, Paris Descartes University, Paris, France.; Ponzo M; Growth, Reparation and Tissue Regeneration Laboratory, Equipe de Recherche Labellisée ERL-CNRS 9215, University of Paris-Est, Créteil, France.; Carpentier G; Growth, Reparation and Tissue Regeneration Laboratory, Equipe de Recherche Labellisée ERL-CNRS 9215, University of Paris-Est, Créteil, France.; Cascone I; Growth, Reparation and Tissue Regeneration Laboratory, Equipe de Recherche Labellisée ERL-CNRS 9215, University of Paris-Est, Créteil, France.; Tomasini R; INSERM U1068/UMR 7258 CNRS, Cancer Research Center of Marseille, Marseille, France.; Schmid HA; Novartis Pharmaceuticals, Basel, Switzerland.; Mathonnet M; Equipe d'Accueil EA 3842 Laboratory, Medicine and Pharmacy Faculties, University of Limoges, Limoges, France.; Nicolle R; Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre Le Cancer, Paris, France.; Bousquet MP; Institute for Pharmacology and Structural Biology, University of Toulouse, Toulouse, France.; Martineau Y; Centre de Recherches en Cancérologie de Toulouse (CRCT), Université de Toulouse, INSERM Unité Mixte de Recherche UMR-1037, CNRS Equipe de Recherche Labellisée ERL5294, Equipe de Recherche Labellisée 'Ligue Contre le Cancer' & 'LabEx Toucan', Toulouse, France.; Pyronnet S; Centre de Recherches en Cancérologie de Toulouse (CRCT), Université de Toulouse, INSERM Unité Mixte de Recherche UMR-1037, CNRS Equipe de Recherche Labellisée ERL5294, Equipe de Recherche Labellisée 'Ligue Contre le Cancer' & 'LabEx Toucan', Toulouse, France.; Jean C; Centre de Recherches en Cancérologie de Toulouse (CRCT), Université de Toulouse, INSERM Unité Mixte de Recherche UMR-1037, CNRS Equipe de Recherche Labellisée ERL5294, Equipe de Recherche Labellisée 'Ligue Contre le Cancer' & 'LabEx Toucan', Toulouse, France.; Bousquet C; Centre de Recherches en Cancérologie de Toulouse (CRCT), Université de Toulouse, INSERM Unité Mixte de Recherche UMR-1037, CNRS Equipe de Recherche Labellisée ERL5294, Equipe de Recherche Labellisée 'Ligue Contre le Cancer' & 'LabEx Toucan', Toulouse, France. Electronic address: corinne.bousquet@inserm.fr.
Source
Publisher: American Gastroenterological Association Country of Publication: United States NLM ID: 101648302 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2352-345X (Electronic) Linking ISSN: 2352345X NLM ISO Abbreviation: Cell Mol Gastroenterol Hepatol Subsets: MEDLINE
Subject
Language
English
Abstract
Background & Aims: Cancer-associated fibroblasts (CAFs) from pancreatic adenocarcinoma (PDA) present high protein synthesis rates. CAFs express the G-protein-coupled somatostatin receptor sst1. The sst1 agonist SOM230 blocks CAF protumoral features in vitro and in immunocompromised mice. We have explored here the therapeutic potential of SOM230, and underlying mechanisms, in immunocompetent models of murine PDA mimicking the heavy fibrotic and immunosuppressive stroma observed in patient tumors.
Methods: Large-scale mass spectrometry analyses were performed on media conditioned from 9 patient PDA-derived CAF primary cultures. Spontaneous transgenic and experimental (orthotopic co-graft of tumor cells plus CAFs) PDA-bearing mice were longitudinally ultrasound-monitored for tumor and metastatic progression. Histopathology and flow cytometry analyses were performed on primary tumors and metastases. Stromal signatures were functionally validated through bioinformatics using several published, and 1 original, PDA database.
Results: Proteomics on the CAF secretome showed that SOM230 controls stromal activities including inflammatory responses. Among the identified secreted proteins, we validated that colony-stimulating factor 1 (CSF-1) (a macrophage growth factor) was reduced by SOM230 in the tumor and plasma of PDA-harboring mice, alongside intratumor stromal normalization (reduced CAF and macrophage activities), and dramatic metastasis reduction. In transgenic mice, these SOM230 benefits alleviate the chemotherapy-induced (gemcitabine) immunosuppressive stroma reshaping. Mechanistically, SOM230 acts in vivo on CAFs through sst1 to disrupt prometastatic CAF production of CSF-1 and cross-talk with macrophages. We found that in patients, stromal CSF-1 was associated with aggressive PDA forms.
Conclusions: We propose SOM230 as an antimetastatic therapy in PDA for its capacity to remodel the fibrotic and immunosuppressive myeloid stroma. This pharmacotherapy should benefit PDA patients treated with chemotherapies.
(Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
Methods: Large-scale mass spectrometry analyses were performed on media conditioned from 9 patient PDA-derived CAF primary cultures. Spontaneous transgenic and experimental (orthotopic co-graft of tumor cells plus CAFs) PDA-bearing mice were longitudinally ultrasound-monitored for tumor and metastatic progression. Histopathology and flow cytometry analyses were performed on primary tumors and metastases. Stromal signatures were functionally validated through bioinformatics using several published, and 1 original, PDA database.
Results: Proteomics on the CAF secretome showed that SOM230 controls stromal activities including inflammatory responses. Among the identified secreted proteins, we validated that colony-stimulating factor 1 (CSF-1) (a macrophage growth factor) was reduced by SOM230 in the tumor and plasma of PDA-harboring mice, alongside intratumor stromal normalization (reduced CAF and macrophage activities), and dramatic metastasis reduction. In transgenic mice, these SOM230 benefits alleviate the chemotherapy-induced (gemcitabine) immunosuppressive stroma reshaping. Mechanistically, SOM230 acts in vivo on CAFs through sst1 to disrupt prometastatic CAF production of CSF-1 and cross-talk with macrophages. We found that in patients, stromal CSF-1 was associated with aggressive PDA forms.
Conclusions: We propose SOM230 as an antimetastatic therapy in PDA for its capacity to remodel the fibrotic and immunosuppressive myeloid stroma. This pharmacotherapy should benefit PDA patients treated with chemotherapies.
(Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)