Pharmacological normalization of pancreatic cancer-associated fibroblast secretome impairs pro-metastatic cross-talk with macrophages: Stromal CSF-1 facilitates metastasis

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 pro-tumoral 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 the media conditioned from nine 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 one original, PDA database. Results Proteomics on the CAF secretome revealed that SOM230 controls stromal activities including inflammatory responses. Amongst the identified secreted proteins, we validated that CSF-1 (macrophage colony-stimulating factor) was reduced by SOM230 in the tumor and plasma of PDA-harboring mice, alongside intra-tumor stromal normalization (reduced CAF and macrophage activities), and dramatic metastasis reduction. In transgenic mice, these SOM230 benefits alleviate the chemotherapy (gemcitabine) -induced immunosuppressive stroma reshaping. Mechanistically, SOM230 acts in vivo on CAFs through sst1 to disrupt pro-metastatic CAF production of CSF-1 and cross-talk with macrophages. We found that in patients, stromal CSF-1 was associated with aggressive PDA forms. Conclusion We propose SOM230 as an anti-metastatic therapy in PDA for its capacity to remodel the fibrotic and immunosuppressive myeloid stroma. This pharmacotherapy should benefit PDA patients treated with chemotherapies.