Stromal oncostatin M cytokine promotes breast cancer progression by reprogramming the tumor microenvironment
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Date
2022-04-01Author
Araujo, Angela M.
Abaurrea, Andrea
Azcoaga, Peio
López Velazco, Joanna I.
Manzano, Sara
Rodríguez Martínez, Javier
Rezola, Ricardo
Egia Mendikute, Leire
Valdés Mora, Fátima
Flores, Juana M.
Jenkins, Liam
Pulido, Laura
Osorio Querejeta, Iñaki
Fernández Nogueira, Patricia
Ferrari, Nicola
Viera, Cristina
Martín Martín, Natalia
Tzankov, Alexandar
Eppenberger Castori, Serenella
Álvarez López, Isabel
Urruticoechea, Ander
Bragado, Paloma
Coleman, Nicholas
Palazón, Asís
Gallego Ortega, David
Calvo González, Fernando
Isacke, Clare M.
Caffarel, María M.
Lawrie, Charles
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Journal of Clinical Investigation 132(7) : (2022) // Article ID e148667
Abstract
[EN] 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.