PO-290 Oncostatin M signalling mediates the crosstalk between cancer cells and tumour microenvironment and promotes breast cancer progression

Abstract

IntroductionCytokines are important players in inflammation, a process highly associated with tumour initiation, tumour growth, angiogenesis and metastasis. Oncostatin M Receptor (OSMR) is a membrane receptor belonging to the interleukin 6 (IL6) receptor family and it has been shown to play a role in inflammation, angiogenesis and tumour progression. In breast cancer it has been associated with the EMT process, key component in cancer progression. While it is clear that cancer cells express the receptor OSMR it seems that the ligand Oncostatin M (OSM) is mainly secreted by the tumour stroma suggesting a possible existence of paracrine signalling between the tumour microenvironment and cancer cells. We previously showed that OSMR is frequently copy-number gained and over-expressed in squamous cell carcinoma, where it induces migration, invasion and metastasis. We now investigate the role of OSMR in breast cancer progression and its importance in mediating the communication with the tumour microenvironment.Material and methodsTo address this issue we used a wide array of tools including in vivo models and in vitro cell cultures of breast cancer cell lines together with co-cultures of stromal cells such as cancer-associated fibroblasts and macrophages. The role of OSMR in oncogenesis and metastasis was studied by generating a mouse line that expresses the PyMT oncogene after the MMTV promoter and lacks OSMR. To address the importance of OSMR pathway in the tumour microenvironment context, we injected murine cells in the mammary gland of OSMR KO and control mice.Results and discussionsThe receptor OSMR is expressed by breast cancer cells while the ligand OSM seems to be mainly produced by cancer associated macrophages and fibroblasts. Depletion of OSMR delays tumour onset, decreases tumour growth and generation of lung metastasis in MMTV-PYMT mice model. Orthotopic injections of murine TS1 cells in OSMR deficient mice shows a decrease in tumour growth compared to control mice, suggesting that OSMR signalling is also important in tumour stroma.ConclusionOur results support that OSMR pathway has an important role in the initiation and progression of breast cancer and that it is important in preparing the tumour microenvironment to facilitate tumourigenesis. OSMR could be blocked by antibody based inhibition, strategy that has had a major impact on breast cancer which makes it a promising candidate for therapeutic targeting.