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bioRxiv · 10.1101/2022.10.26.513889

Tumor-educated Gr1+CD11b+ cells instigate breast cancer metastasis by twisting cancer cells plasticity via OSM/IL6-JAK signaling

Peyvandi, S.·Bulliard, M.·Kauzlaric, A.·Coquoz, O.·Huang, Y.-t.·Duffey, N.·Gafner, L.·Lorusso, G.·Fournier, N.·Lan, Q.·Rüegg, C.
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Abstract

Cancer cell plasticity contributes to tumor therapy resistance and metastasis formation, which represent the main causes of cancer-related death for most cancers, including breast cancer. The tumor microenvironment drives cancer cell plasticity and metastasis and, thus, unravelling the underlying cues may provide novel effective strategies to manage metastatic disease. Here, we show that stem cell antigen-1 positive (Sca-1+) murine breast cancer cells enriched during tumor progression and metastasis have higher in vitro cancer stem cell-like properties, enhanced in vivo metastatic ability, and initiate primary tumors rich in Gr1highCD11b+Ly6Clow cells. In turn, tumor-educated Gr1+CD11b+ (Tu-Gr1+CD11b+) cells rapidly and transiently convert low metastatic 4T1-Sca-1- cells into highly metastatic 4T1-Sca-1+ cells via secreted OSM and IL6. Moreover, chemotherapy- resistant and highly metastatic 4T1-derived cells maintain high Sca-1+ frequency through cell autonomous IL6 production. Inhibition of OSM, IL6 or JAK suppressed Tu-Gr1+CD11b+-induced Sca-1+ population enrichment in vitro, while JAK inhibition abrogated metastasis of chemotherapy-enriched Sca-1+ cells in vivo. Importantly, Tu-Gr1+CD11b+ cells invoked a gene signature in tumor cells predicting shorter OS and RFS in breast cancer patients. Collectively, our data identified OSM/IL6-JAK as a clinically relevant paracrine/autocrine axis instigating breast cancer cell plasticity triggering metastasis.

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Peyvandi, S., Bulliard, M., Kauzlaric, A., Coquoz, O., Huang, Y.-t., Duffey, N., Gafner, L., Lorusso, G., Fournier, N., Lan, Q., Rüegg, C.. 2022-10-27. Tumor-educated Gr1+CD11b+ cells instigate breast cancer metastasis by twisting cancer cells plasticity via OSM/IL6-JAK signaling. https://doi.org/10.1101/2022.10.26.513889

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