Related Experiment Video
Updated: Nov 20, 2025
A Mouse Model to Investigate the Role of Cancer-Associated Fibroblasts in Tumor Growth
Published on: December 22, 2020
Pharmacologic Normalization of Pancreatic Cancer-Associated Fibroblast Secretome Impairs Prometastatic Cross-Talk
Rémi Samain1, Alexia Brunel1, Thibault Douché1
1Centre 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.
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.
Insights
SOM230 therapy targets cancer-associated fibroblasts (CAFs) in pancreatic cancer by reducing pro-metastatic factors like CSF-1. This approach remodels the tumor stroma, reduces metastasis, and may enhance chemotherapy effectiveness.
Area of Science:
- Oncology
- Cancer Biology
- Immunology
Background:
- Pancreatic ductal adenocarcinoma (PDA) is characterized by a dense, immunosuppressive tumor stroma.
- Cancer-associated fibroblasts (CAFs) within the PDA stroma exhibit high protein synthesis and express the somatostatin receptor sst1.
- The sst1 agonist SOM230 has demonstrated potential in inhibiting CAF protumoral activities.
Purpose of the Study:
- To investigate the therapeutic potential of SOM230 in immunocompetent murine models of PDA.
- To elucidate the underlying mechanisms by which SOM230 modulates the tumor microenvironment.
- To assess the impact of SOM230 on fibrotic and immunosuppressive stromal components in PDA.
Main Methods:
- Proteomic analysis of CAF secretomes from patient-derived cultures.
- Utilized spontaneous transgenic and experimental orthotopic PDA mouse models.
- Longitudinal ultrasound monitoring, histopathology, flow cytometry, and bioinformatics analyses were employed.
Main Results:
- SOM230 treatment reduced colony-stimulating factor 1 (CSF-1) production by CAFs, a key factor in macrophage recruitment.
- Intratumoral stromal normalization, characterized by reduced CAF and macrophage activity, and significant metastasis reduction were observed.
- SOM230 alleviated chemotherapy-induced immunosuppressive stromal remodeling in transgenic mice.
Conclusions:
- SOM230 demonstrates significant antimetastatic potential in PDA by remodeling the fibrotic and immunosuppressive myeloid stroma.
- Targeting CAFs with SOM230 offers a promising therapeutic strategy for PDA patients, potentially enhancing the efficacy of chemotherapy.
More Related Videos
Related Concept Videos
02:17The Tumor Microenvironment
01:19Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...