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.
View: Text | PDF | Corrigendum
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

×

Figure 8

OSM/OSMR signaling induces myeloid recruitment.

Options: View larger image (or click on image) Download as PowerPoint
OSM/OSMR signaling induces myeloid recruitment. (A) Effect of conditione...
(A) Effect of conditioned media from CAF-173 treated with PBS (control) or 10 ng/mL OSM for 72 hours on HL-60–derived monocyte migration, n = 4 independent experiments. (B) Representative pictures and quantification of F4/80 immunohistochemical staining in tumors derived from MDA-MB-231/CAF-173 coinjections described in Figure 6A. Quantification was performed by manual counting of positive cells per area in a total of 12 to 19 pictures per tumor and 4 to 7 tumors per group. Scale bars: 100 μm (large pictures) and 10 μm (insets). (C) Representative pictures and quantification of F4/80 and Ly6G immunohistochemical staining in tumors from MMTV-PyMT Osmr-WT, -HET, and -KO mice at 14 weeks of age, described in Figure 1A. Quantification was performed by manual counting of positive cells per area in a total of 8 pictures per tumor and 5 tumors per group. Scale bars: 50 μm. (D) VEGF, CXCL1, and CXCL16 levels in plasma from MMTV-PyMT Osmr-WT, -HET, and -KO mice at 14 weeks of age analyzed by Luminex assay. In A–D, P values between the different groups were determined using paired (A) or unpaired (B) 2-tailed Student’s t test, 1-way ANOVA (C), or 1-way ANOVA with post hoc Dunnett’s multiple-comparison test (D). (E) Correlation of OSM and OSMR levels with VEGF, CXCL1, and CXCL16 expression in breast cancer samples. Data were downloaded from the TIMER web platform (n = 1,100). Spearman’s correlation coefficients and P values are shown. TPM, transcript count per million reads. (F) Kaplan-Meier curves showing overall survival (OS) for breast cancer samples according to the expression of VEGF, CXCL1, and CXCL16. Data were downloaded from Kaplan-Meier Plotter. P value was determined using the Mantel-Cox test and high and low expression levels were stratified by median value.