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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 Article has an altmetric score of 72

Tumor-educated Gr1+CD11b+ cells drive breast cancer metastasis via OSM/IL-6/JAK–induced cancer cell plasticity

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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 2

SCA1 expression is modulated by TME.

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SCA1 expression is modulated by TME.
(A) Frequency of different immune c...
(A) Frequency of different immune cell populations in PTs of mice orthotopically injected with 4T1-SCA1+ and 4T1-SCA1– cells 21 days after injection. Populations are determined in CD45-positive, viable cells. n = 8 mice/group. (B and C) Schematic (B) showing experimental design for isolating Gr1+ cells from different sites of tumor-bearing mice. Twenty-one days after tumor implantation, Gr1+ cells were isolated from bone marrow (BM-Gr1+CD11b+), spleen (Spl- Gr1+CD11b+), or PT (Tu-Gr1+CD11b+) and cocultured for 48 hours with parental 4T1 or sorted 4T1-SCA1– cells in vitro. SCA1 expression in tumor cells was examined by flow cytometry (C). Coculture conditions are indicated in bar graph. n = 3/group for 4T1; n = 5–9/group for 4T1-SCA1–. (D and E) Schematic of experimental coculture setup (E). MACS-enriched Gr1+ cells were cocultured with 4T1 or sorted 4T1-SCA1– cells with or without Transwell inserts of 0.4 μm pore size. Cells were seeded in bottom well and Gr1+CD11b+ cells in upper part of insert. After 48 hours, tumor cells were examined for SCA1 expression by FACS (E). Coculture conditions are indicated in bar graph. Ratio of tumor cells and Tu-Gr1+CD11b+ varied from 1:1 to 1:3. n = 3/group for 4T1; n = 5–9/group for 4T1-SCA1–. (F–H) Schematic of experimental metastasis setup for evaluation of metastatic capacity of Gr1+CD11b+-educated 4T1 cells in vivo (F). 4T1 tumor cells were primed with Tu-Gr1+CD11b+ or Spl-Gr1+CD11b+ in vitro without cell-cell contact for 48 hours and injected into tail veins. Lung metastases were quantified 10 days after injection (G). Representative H&E staining images of lung sections are shown (H). Scale bar: 1 mm. n = 6 mice/group. Data are represented as means ± SEM and are representative of 3 independent experiments. P values were calculated using unpaired 2-tailed Student’s t test (A and H) or 1-way ANOVA with Dunnett’s multiple-comparison test (C and E). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.

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