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bioRxiv · 10.1101/2024.10.11.617845

TGFβ1-TNFα regulated secretion of neutrophil chemokines is independent of epithelial-mesenchymal transitions in breast tumor cells

Sengupta, S.·Cohen, E.·Serrenho, J.·Ott, K.·Coulombe, P. A.·Parent, C.
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Abstract

Neutrophils have tumor-promoting roles in breast cancer and are detected in higher numbers in aggressive breast tumors. How aggressive breast tumors recruit neutrophils remains undefined. Here, we investigated the roles of TGF-{beta}1 and TNF- in the regulation of neutrophil recruitment by breast cancer cells. TGF-{beta}1 and TNF- are pro-inflammatory factors upregulated in breast tumors and induce epithelial to mesenchymal transitions (EMT), a process linked to cancer cell aggressiveness. We report that, as expected, dual treatment with TGF-{beta}1 and TNF- induces EMT signatures in premalignant M2 cells, which are part of the MCF10A breast cancer progression model. Conditioned media (CM) harvested from M2 cells treated with TGF-{beta}1/TNF- gives rise to amplified neutrophil chemotaxis compared to CM from control M2 cells. This response correlates with higher levels of the neutrophil chemokines CXCL1, CXCL2, and CXCL8 and is significantly attenuated in the presence of a CXCL8-neutralizing antibody. Furthermore, we found that secretion of CXCL1 and CXCL8 from treated M2 cells depends on p38MAPK activity. By combining gene editing, immunological and biochemical approaches, we show that the regulation of neutrophil recruitment and EMT signatures are not mechanistically linked in treated M2 cells. Finally, analysis of publicly available cancer cell line transcriptomic databases revealed a significant correlation between CXCL8 and TGF-{beta}1/TNF--regulated or effector genes in breast cancer. Together, our findings establish a novel role for the TGF-{beta}1/TNF-/p38 MAPK signaling axis in regulating neutrophil recruitment in breast cancer, independent of TGF-{beta}1/TNF- regulated EMT.

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Sengupta, S., Cohen, E., Serrenho, J., Ott, K., Coulombe, P. A., Parent, C.. 2024-10-12. TGFβ1-TNFα regulated secretion of neutrophil chemokines is independent of epithelial-mesenchymal transitions in breast tumor cells. https://doi.org/10.1101/2024.10.11.617845

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