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 4

Transformation dynamics of tumor cell populations induced by the TME.

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Transformation dynamics of tumor cell populations induced by the TME. (A...
(A) UMAP plots showing 4T1 clusters based on integrated scRNA-Seq data from 4T1 cells in 3D culture or in PT. (B) Distribution of specific clusters in 4T1 cells in 3D culture or PT. (C and D) UMAP plot (C) and box plot (D) showing the clusters in pseudo-time course during the transformation of 4T1 cells from ex vivo culture to in vivo. (E) Sankey diagram showing the dynamic of each cluster during the transformation of 4T1 cells from ex vivo culture to in vivo. Cluster 3 was largely expanded in vivo. (F) UMAP plots showing MCF-7 clusters based on integrated scRNA-Seq data from MCF-7 cells in culture or in PT. (G) Distribution of the specific clusters in cultured MCF-7 cells or MCF-7 PTs. (H–I) UMAP plot (H) and box plot (I) showing the clusters in pseudo-time course during the transformation of MCF-7 cells from ex vivo culture to in vivo. (J) Sankey diagram showing the dynamic of each cluster during the transformation of MCF-7 cells from ex vivo culture to in vivo. Clusters 2 and 4 were largely expanded in vivo. (K and L) GSEA analysis of SCA1-positive signature, SCA1-negative signature, and Tu-Gr1+CD11b+–induced signature of cells in cluster 3 in 4T1 data (K) and in cluster 2 and cluster 4 in MCF-7 data (L). Analyses are based on publicly available data (4T1: GEO GSM4812003 and GSM3502134; MCF-7: GEO GSM4681765 and GSM5904917).