Stromal oncostatin M cytokine promotes breast cancer progression by reprogramming the tumor microenvironment
Angela M. Araujo, … , María M. Caffarel, Charles H. Lawrie
Angela M. Araujo, … , María M. Caffarel, Charles H. Lawrie
Published February 22, 2022
Citation Information: J Clin Invest. 2022;132(7):e148667. https://doi.org/10.1172/JCI148667.
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Research Article Inflammation Oncology

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

Abstract

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.

Authors

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

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Figure 2

The stromal OSM/OSMR axis promotes breast cancer progression.

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The stromal OSM/OSMR axis promotes breast cancer progression. (A) Experi...
(A) Experimental setup of the in vivo experiment designed to assess the importance of OSMR signaling in the tumor microenvironment, in which TS1 cells were orthotopically injected into the mammary fat pad of Osmr-WT and -KO mice. (B–E) Kaplan-Meier curves for tumor-free survival (B), tumor growth (C), and final tumor volume (D) and weight (E) after dissection of orthotopic tumors described in A. Two independent experiments were performed, and the results were combined in B, D, and E. (F and G) OSM and OSMR mRNA expression in paired cancer epithelial versus cancer stroma (F, GSE10797) and normal stroma versus cancer stroma breast cancer samples (G, GSE9014). Data were downloaded from NCBI GEO data sets. P values were calculated using the Mantel-Cox test (B), 2-way ANOVA with post hoc Sidak’s multiple-comparison test (C), or unpaired, 2-tailed Student’s t test (D–G). ***P < 0.001, ****P < 0.0001 for experiment 1 and #P < 0.05, ##P < 0.01,####P < 0.001 for experiment 2.