Pharmacologic Normalization of Pancreatic Cancer-Associated Fibroblast Secretome Impairs Prometastatic Cross-Talk With Macrophages
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.
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BibTeX
@article{samain2026pharmacologic,
title = {{Pharmacologic Normalization of Pancreatic Cancer-Associated Fibroblast Secretome Impairs Prometastatic Cross-Talk With Macrophages}},
author = {Rémi Samain and Alexia Brunel and Thibault Douché and Marjorie Fanjul and Stéphanie Cassant-Sourdy and Julia Rochotte and Jérôme Cros and Cindy Neuzillet and Jérôme Raffenne and Camille Duluc and Aurélie Perraud and Jérémy Nigri and Véronique Gigoux and Ivan Bieche and Matteo Ponzo and Gilles Carpentier and Ilaria Cascone and Richard Tomasini and Herbert Schmid and Muriel Mathonnet and Rémy Nicolle and Marie-Pierre Bousquet and Yvan Martineau and Stéphane Pyronnet and Christine Jean and Corinne Bousquet},
journal = {Cellular and Molecular Gastroenterology and Hepatology},
year = {2026},
month = oct,
doi = {10.1016/j.jcmgh.2021.01.008},
url = {https://hal.science/hal-05801552v1},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Pharmacologic Normalization of Pancreatic Cancer-Associated Fibroblast Secretome Impairs Prometastatic Cross-Talk With Macrophages
AU - Rémi Samain
AU - Alexia Brunel
AU - Thibault Douché
AU - Marjorie Fanjul
AU - Stéphanie Cassant-Sourdy
AU - Julia Rochotte
AU - Jérôme Cros
AU - Cindy Neuzillet
AU - Jérôme Raffenne
AU - Camille Duluc
AU - Aurélie Perraud
AU - Jérémy Nigri
AU - Véronique Gigoux
AU - Ivan Bieche
AU - Matteo Ponzo
AU - Gilles Carpentier
AU - Ilaria Cascone
AU - Richard Tomasini
AU - Herbert Schmid
AU - Muriel Mathonnet
AU - Rémy Nicolle
AU - Marie-Pierre Bousquet
AU - Yvan Martineau
AU - Stéphane Pyronnet
AU - Christine Jean
AU - Corinne Bousquet
PY - 2026
DA - 2026/10/15
JO - Cellular and Molecular Gastroenterology and Hepatology
DO - 10.1016/j.jcmgh.2021.01.008
UR - https://hal.science/hal-05801552v1
AB - 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.
SN - 2352-345X
ER -