Journal Article

Stromal oncostatin M cytokine promotes breast cancer progression by reprogramming the tumor microenvironment

Coleman, Nicholas, Gallego-Ortega, David, Isacke, Clare M., Carracedo, Arkaitz, Osorio-Querejeta, Iñaki, Alvarez-Lopez, Isabel, Lawrie, Charles H., Viera, Cristina, Pulido, Laura, Manzano, Sara, Abaurrea, Andrea, Calvo, Fernando, Rezola, Ricardo, Martín-Martín, Natalia, Tzankov, Alexandar, Araujo, Angela M., Fernández-Nogueira, Patricia, López-Velazco, Joanna I., Egia-Mendikute, Leire, Flores, Juana M., Ferrari, Nicola, Rodriguez, Javier, Palazón, Asís, Valdés-Mora, Fátima, Eppenberger-Castori, Serenella, Urruticoechea, Ander, Bragado, Paloma, Caffarel, María M., Jenkins, Liam, Azcoaga, Peio

2022

Overview

The tumor microenvironment (TME) is reprogrammed by cancer cells and participates in all stages of tumor progression. The contribution of stromal cells to the reprogramming of the TME is not well understood. Here, we provide evidence of the role of the cytokine oncostatin M (OSM) as central node for multicellular interactions between immune and nonimmune stromal cells and the epithelial cancer cell compartment. OSM receptor (OSMR) deletion in a multistage breast cancer model halted tumor progression. We ascribed causality to the stromal function of the OSM axis by demonstrating reduced tumor burden of syngeneic tumors implanted in mice lacking OSMR. Single-cell and bioinformatic analysis of murine and human breast tumors revealed that OSM expression was restricted to myeloid cells, whereas OSMR was detected predominantly in fibroblasts and, to a lower extent, cancer cells. Myeloid-derived OSM reprogrammed fibroblasts to a more contractile and tumorigenic phenotype and elicited the secretion of VEGF and proinflammatory chemokines CXCL1 and CXCL16, leading to increased myeloid cell recruitment. Collectively, our data support the notion that the stromal OSM/OSMR axis reprograms the immune and nonimmune microenvironment and plays a key role in breast cancer progression.

• Publisher: American Society for Clinical Investigation
• Subject: Animals / Biomedical research / Breast cancer / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Cancer / Cell differentiation / Chemokines / Connective tissue cells / Contractility / CXCL16 protein / Cytokines / Development and progression / Extracellular matrix / Female / Fibroblasts / Fibroblasts - metabolism / Gene expression / Genetic aspects / Growth factors / Health aspects / Humans / Immune system / Inflammation / Metastasis / Mice / Myeloid cells / Oncology / Oncology, Experimental / Oncostatin M / Oncostatin M - genetics / Oncostatin M - metabolism / Phenotypes / Signal Transduction / Stromal cells / Tumor Microenvironment / Tumors / Vascular endothelial growth factor