Stromal oncostatin M cytokine promotes breast cancer progression by reprogramming the tumor microenvironment
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
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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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 1

Deletion of OSMR in the MMTV-PyMT model hampers tumor progression and reduces metastasis.

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Deletion of OSMR in the MMTV-PyMT model hampers tumor progression and re...
(A) Experimental set-up of the in vivo experiment designed to assess the importance of OSMR signaling in disease progression of the MMTV-PyMT mouse model. F0, F1, and F2 are different filial generations. (B–D) Kaplan-Meier curves for tumor-free survival (B), tumor growth (C), and final tumor burden (D) in MMTV-PyMT Osmr-WT, MMTV-PyMT Osmr-HET (heterozygous), and MMTV-PyMT Osmr-KO mice. (E) Histopathological analysis of tumors at week 14. Graph represents percentage of mice bearing carcinomas, adenomas, hyperplasia, and no lesions in mammary glands. P value was determined by comparing the number of mice with malignant carcinoma versus nonmalignant phenotypes (adenoma, hyperplasia) and no lesions using the χ2 test. (F and G) Western blot (F) and densitometric analysis (G) of fibronectin (FN) protein levels in tumors at week 14 from animals of the different genotypes. (H) Percentage of animals with lung metastases at 14 weeks of age. P value was determined by comparing animals with metastasis (macro and micro) versus without metastasis using the χ2 test. (I) Representative pictures of lung metastases at week 14 in MMTV-PyMT Osmr-WT, -HET, and -KO animals. Metastatic nodules are indicated with red arrows. Scale bars: 200 μm (top and middle rows) and 50 μm (bottom row). P values were calculated using the Mantel-Cox test (B), 2-way ANOVA with post hoc Dunnett’s multiple-comparison test (C), or 1-way ANOVA test (D and G). *P < 0.01; ***P < 0.001; ****P < 0.0001 KO vs. WT and #P < 0.05 HET vs. WT.