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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

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 8

Tu-Gr1+CD11b+–induced tumor cell signature predicts worse outcome in breast cancer patients.

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Tu-Gr1+CD11b+–induced tumor cell signature predicts worse outcome in bre...
(A) Box plot showing the expression of Tu-Gr1+CD11b+–induced 4T1 cell signature in PT and lung metastasis in the 4T1, 6DT1, Mvt1, and Met1 murine metastatic breast cancer models, extracted from the Ross data set (39). The box extended from 25th to 75th percentile, with the median indicated as a line within the box. The whiskers shown are 1.5 times interquartile ranges. P values were calculated using unpaired 2-tailed Student’s t test. (B) Expression of human orthologue of Tu-Gr1+CD11b+–induced signature in breast cancer patients with (yes) or without (no) metastatic relapse to the lung in the NKI295 cohort (58). (C and D) Kaplan-Meier curves showing OS (C) or RFS (D) for breast cancer patients according to high or low expression of an orthologue 32 gene signature, based on the Tu-Gr1+CD11b+–induced 4T1 cell signature in the METABRIC data sets (59). (E and F) Forest plots showing Cox’s proportional hazard regression (HR) for OS (E) and RFS (F) of the individual 32 orthologues of the Tu-Gr1+CD11b+–induced signature, based on gene expression in tumor samples of the METABRIC data set. (G and H) Kaplan-Meier curves showing OS (G) and RFS (H) according to the minimal 5-gene orthologue gene signature expression in the METABRIC data sets. P values were calculated using unpaired 2-tailed Student’s t test (A and B) or log-rank test (C, D, G and H). *P < 0.05; **P < 0.01.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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