| Autor: |
A. Abaurrea, Arkaitz Carracedo, Azcoaga P, Alexandar Tzankov, Rezola R, López-Velazco Ji, Charles H. Lawrie, Juana M. Flores, María M. Caffarel, Alvarez-Lopez I, Liam Jenkins, David Gallego-Ortega, Paloma Bragado, Iñaki Osorio-Querejeta, Eppenberger-Castori S, Fatima Valdes-Mora, Clare M. Isacke, Ander Urruticoechea, Nicholas Coleman, Fernando Calvo, Nicola Ferrari, Natalia Martín-Martín, Angela M Araujo, Patricia Fernández-Nogueira |
| Rok vydání: |
2020 |
| Předmět: |
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| DOI: |
10.1101/2020.10.30.356774 |
| Popis: |
Cancer cells are constantly communicating with the surrounding tumour microenvironment (TME) and they hijack physiological cell interactions to overcome immune system surveillance and promote cancer progression1,2. However, the contribution of stromal cells to the reprogramming of the TME is not well understood. In this study we provide unprecedented evidence of the role of the cytokine Oncostatin M (OSM) as central node for multicellular interactions between immune and non-immune stroma and the epithelial compartment. We show that stromal expression of the OSM:Oncostatin M Receptor (OSMR) axis plays a key role in breast cancer progression. OSMR deletion in a multistage breast cancer model delays tumour onset, tumour growth and reduces metastatic burden. We ascribed causality to the stromal function of OSM axis by demonstrating reduced tumour burden of syngeneic tumours implanted in mice. Single-cell and bioinformatic analysis of murine and human breast tumours revealed that the expression of OSM signalling components is compartmentalized in the tumour stroma. OSM expression is restricted to myeloid cells, whereas OSMR expression is detected predominantly in fibroblasts and, to a lower extent, cancer cells. Myeloid-derived OSM reprograms fibroblasts to a more contractile and pro-tumorigenic phenotype, elicits the secretion of VEGF and pro-inflammatory chemokines (e.g. CXCL1 and CXCL16), leading to increased neutrophil and macrophage recruitment. In summary, our work sheds light on the mechanism of immune regulation by the tumour microenvironment, and supports that targeting OSM:OSMR interactions is a potential therapeutic strategy to inhibit tumour-promoting inflammation and breast cancer progression. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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