Tumoral hypoxic extracellular vesicles create a protective microenvironment for triple-negative breast cancer

Pachane, B. C.; Bottaro, P. H. T.; Machado, A. M.; Castro, C. A.; Guerra, G.; Gozzer, L. T.; Grigoli, M. M.; Zutiao, A. D.; Fuzer, A. M.; Cominetti, M. R.; Altei, W. F.; Selistre-de-Araujo, H. S.

doi:10.1101/2024.11.01.621519

bioRxiv · 10.1101/2024.11.01.621519

Tumoral hypoxic extracellular vesicles create a protective microenvironment for triple-negative breast cancer

Pachane, B. C.·Bottaro, P. H. T.·Machado, A. M.·Castro, C. A.·Guerra, G.·Gozzer, L. T.·Grigoli, M. M.·Zutiao, A. D.·Fuzer, A. M.·Cominetti, M. R.·Altei, W. F.·Selistre-de-Araujo, H. S.

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Abstract

The highly metastatic triple-negative breast cancer (TNBC) relies on the tumor microenvironment (TME) to maintain phenotypic heterogeneity and progression. Extracellular vesicles from hypoxic TNBC (EVh) have been previously shown to facilitate tumoral invasion; however, their function in the tumor microenvironment remains unclear. We used a novel method to investigate the TME in vitro called multicellular circulating co-culture, to characterize how EVh interferes with tumoral and endothelial cells, fibroblasts, monocytes and macrophages. EVh promoted monocyte differentiation to M2-like macrophages and inhibited macrophage-derived phagocytosis in endothelial and tumoral cells. The protection of endothelial, tumoral and stromal cellular integrity by EVh increased pro-tumoral and pro-angiogenic signaling, collagen matrix synthesis and showed a potential differentiation to cancer-associated fibroblasts. Our findings highlight the critical role of EVh in protecting tumor cells, indicating its cooperation towards a protective TME, which was demonstrated by the multicellular circulating co-culture and conventional co-culture protocols. These findings lead to an adequate system with potential for investigating other tumor-related processes, including circulating tumor cells and metastasis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/621519v3_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@4ff8a0org.highwire.dtl.DTLVardef@4bf15corg.highwire.dtl.DTLVardef@1d2f105org.highwire.dtl.DTLVardef@1cd8346_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Pachane, B. C., Bottaro, P. H. T., Machado, A. M., Castro, C. A., Guerra, G., Gozzer, L. T., Grigoli, M. M., Zutiao, A. D., Fuzer, A. M., Cominetti, M. R., Altei, W. F., Selistre-de-Araujo, H. S.. 2024-11-04. Tumoral hypoxic extracellular vesicles create a protective microenvironment for triple-negative breast cancer. https://doi.org/10.1101/2024.11.01.621519

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