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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Research Article Oncology

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 5

SCA1+ population is modulated by OSM/IL-6/JAK pathway.

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SCA1+ population is modulated by OSM/IL-6/JAK pathway. (A) Relative Osm ...
(A) Relative Osm and Il6 mRNA expression in Tu-Gr1+CD11b+ and Spl-Gr1+CD11b+ cells. n = 4–5/group. (B and C) OSM and IL-6 protein quantification in supernatant of (B) Tu-Gr1+CD11b+ and Spl-Gr1+CD11b+ (C) and Tu-Gr1hiLy6G+CD11b+ and Gr1loLy6G–CD11b+ cells. n = 4/group. (D) Fraction of SCA1+ cells of parental 4T1 or sorted 4T1-SCA1– cells upon exposure to OSM or IL-6 (10 ng/ml 48 hours). n = 6/group. (E) Effect of inhibition of OSM and IL-6 in Tu-Gr1+CD11b+ conditioned medium on SCA1 expression in parental 4T1 or sorted 4T1-SCA1– cells after 48 hours treatment. n = 3–6/group. (F) Experimental design for examining lung metastatic capacity of IL-6/OSM. 4T1-SCA1– cells were primed by Tu-Gr1+CD11b+ conditioned medium with dual depletion of OSM/IL-6 depleted or control, in vitro for 48 hours and then injected into tail vein. Lungs were examined for metastasis 10 days later. (G and H) Quantification of lung metastases (G) and representative H&E staining images of lung sections (H). n = 8–10/group. Scale bar: 1 mm. (I and J) Quantification of lung metastases in mice injected with 4T1 control and 4T1 silenced for Sca1 (shSca1-120 and shSca1-597) (I). n = 8/group. Representative H&E stained lung sections (J). Scale bar: 1 mm. (K) SCA1+ population stimulation in cultured parental 4T1 or sorted 4T1-SCA1– cells by recombinant OSM or IL-6 (10 ng/ml, 48 hours) in vitro in presence of ruxolitinib (5 μM) or DMSO control. n = 3–6/group. Data are represented as means ± SEM from 3 independent experiments. P values were calculated using unpaired 2-tailed Student’s t test (A–C and G); unpaired 2-tailed Student’s t test with Holm’s correction (I); 1-way ANOVA with Dunnett’s multiple-comparison test (D and K); or 1-way ANOVA with Tukey’s multiple-comparison test (E). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.