Tumor-educated Gr1+CD11b+ cells drive breast cancer metastasis via OSM/IL-6/JAK–induced cancer cell plasticity
Sanam Peyvandi, … , Qiang Lan, Curzio Rüegg
Sanam Peyvandi, … , Qiang Lan, Curzio Rüegg
Published January 18, 2024
Citation Information: J Clin Invest. 2024;134(6):e166847. https://doi.org/10.1172/JCI166847.
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Tumor-educated Gr1+CD11b+ cells drive breast cancer metastasis via OSM/IL-6/JAK–induced cancer cell plasticity

Abstract

Cancer cell plasticity contributes to therapy resistance and metastasis, which represent the main causes of cancer-related death, including in breast cancer. The tumor microenvironment drives cancer cell plasticity and metastasis, and unraveling the underlying cues may provide novel strategies for managing metastatic disease. Using breast cancer experimental models and transcriptomic analyses, we show that stem cell antigen-1 positive (SCA1+) murine breast cancer cells enriched during tumor progression and metastasis had higher in vitro cancer stem cell–like properties, enhanced in vivo metastatic ability, and generated tumors rich in Gr1hiLy6G+CD11b+ cells. In turn, tumor-educated Gr1+CD11b+ (Tu-Gr1+CD11b+) cells rapidly and transiently converted low metastatic SCA1– cells into highly metastatic SCA1+ cells via secreted oncostatin M (OSM) and IL-6. JAK inhibition prevented OSM/IL-6–induced SCA1+ population enrichment, while OSM/IL-6 depletion suppressed Tu-Gr1+CD11b+–induced SCA1+ population enrichment in vitro and metastasis in vivo. Moreover, chemotherapy-selected highly metastatic 4T1 cells maintained high SCA1+ positivity through autocrine IL-6 production, and in vitro JAK inhibition blunted SCA1 positivity and metastatic capacity. Importantly, Tu-Gr1+CD11b+ cells invoked a gene signature in tumor cells predicting shorter overall survival (OS), relapse-free survival (RFS), and lung metastasis in breast cancer patients. Collectively, our data identified OSM/IL-6/JAK as a clinically relevant paracrine/autocrine axis instigating breast cancer cell plasticity and triggering metastasis.

Authors

Sanam Peyvandi, Manon Bulliard, Alev Yilmaz, Annamaria Kauzlaric, Rachel Marcone, Lisa Haerri, Oriana Coquoz, Yu-Ting Huang, Nathalie Duffey, Laetitia Gafner, Girieca Lorusso, Nadine Fournier, Qiang Lan, Curzio Rüegg

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Figure 3

Transcriptomic analysis of SCA1+ tumor cells.

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Transcriptomic analysis of SCA1+ tumor cells. (A) Heatmap showing the si...
(A) Heatmap showing the signature score of the hallmark pathways analysis in 4T1-SCA1+ and 4T1-SCA1– populations sorted from parental 4T1 cells. The colors code the expression levels relative to average levels, as indicated at the bottom. (B) Heatmap showing the signature score of the hallmarks pathway analysis in parental 4T1, Spl-Gr1+CD11b+–primed 4T1, and Tu-Gr1+CD11b+–primed 4T1 cells. The colors code the expression levels relative to average levels, as indicated at the bottom. (C) GSEA comparing the Tu-Gr1+CD11b+– and Spl-Gr1+CD11b+–primed 4T1 cells. GSEA shows positive correlations of both SCA1-positive and SCA1-negative signatures. NES, normalized enrichment score. (D) Venn diagrams showing that 56 upregulated genes and 1 downregulated gene are shared between inherent and Tu-Gr1+CD11b+–induced SCA1+ population in 4T1 tumor cells. (E) UMAP plot showing clusters of cancer cells and myeloid cell populations in orthotopically grown 4T1-derived PTs extracted from the Sebastian data set (see Methods for details). (F) Circos diagram showing the predicted potential interactions between cancer cells and different myeloid cell populations determined by CellPhoneDB (see Supplemental Methods for details) based on the Sebastian data set. Only Osmr and P2ry6 are shared with the common 56 gene list shown in panel D.