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

Abstract

The tumour microenvironment (TME) is reprogrammed by cancer cells and participates in all stages of tumour progression. The contribution of stromal cells to the reprogramming of the TME is not well-understood. Here we provide solid 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. Oncostatin M Receptor (OSMR) deletion in a multistage breast cancer model halted tumour progression. We ascribed causality to the stromal function of OSM axis by demonstrating reduced tumour burden of syngeneic tumours implanted in mice lacking OSMR. Single-cell and bioinformatic analysis of murine and human breast tumours 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, elicited the secretion of VEGF and pro-inflammatory chemokines CXCL1 and CXCL16, leading to increased neutrophil and macrophage recruitment. Collectively, our data support that stromal OSM:OSMR axis reprograms the immune and non-immune microenvironment and plays a key role in breast cancer progression.

Tumor-educated Gr1+CD11b+cells instigate breast cancer metastasis by twisting cancer cells plasticity via OSM/IL6–JAK signaling

“…As the IL6-JAK-STAT3 signaling pathway was upregulated both in the 4T1-Sca-1 + population and Tu-Gr1 + CD11b + -primed 4T1 cells (Figure 3A, B), we next examined the expression of Osm , Osmr , Il6st , Il6 , and Il6 receptor ( Il6ra ) in the Sebastian dataset (Figure 3G). The expression of Il6 and Osm was restricted to myeloid cells, with Osm expression being more prominent, similar to a previous report (33). Osmr was predominantly expressed in tumor cells, while Il6st and Il6ra were homogenously expressed in all cell types.…”

“…Besides directly activating tumor cells, OSM has also been shown to remodel macrophages and fibroblasts of the TME (33, 36). Araujo et al recently reported that OSM derived from tumor-infiltrating myeloid cells reprogram fibroblasts to secrete VEGF and the chemokines CXCL1 and CXCL16, resulting in enhanced myeloid cell recruitment and breast cancer progression (33).…”

“…Increased OSM or IL6 expression correlates with reduced survival in breast cancer patients (30, 31). OSM was shown to drive breast cancer progression and metastasis through direct effects on cancer cells, such as suppression of estrogen receptor (ER) expression (31) and promotion of EMT (25, 32), and indirect effects via TME cells, in particular the reprogramming of tumor associated macrophages and fibroblasts (33–36).…”

Integrated Analysis of Multiomics Data Identified Molecular Subtypes and Oxidative Stress-Related Prognostic Biomarkers in Glioblastoma Multiforme

“…However, in some cases, OSM can promote tumor progression. Overexpression of OSM and OSMR has been detected in various cancers, including gastric, colorectal, breast, and glioma [ 38 , 39 ]. OSM-OSMR signal transduction plays a vital role in inflammation, oxidative stress, hematopoiesis, and development and is increasingly considered an essential factor in tumor progression [ 40 ].…”

Oncostatin M: From Intracellular Signaling to Therapeutic Targets in Liver Cancer

“…In breast carcinoma, hypoxic epithelial tumor cells overexpress and release high levels of OSM, favoring the recruitment and M2 polarization of macrophages [ 54 ]. Moreover, myeloid-cell-derived OSM can drive CAFs to a pro-carcinogenic phenotype, showing increased contractility and secretion of soluble mediators, leading to immune cells’ accumulation and further supporting breast cancer development [ 55 ].…”