Chemotherapy-induced extracellular vesicle miRNAs promote breast cancer stemness by targeting OneCUT2

Abstract

Cancer-secreted, extracellular vesicle (EV)–encapsulated miR-195-5p, and miR-203a-3p in circulating EV and miRNAs enable cancer cells to communicate with each decreased ONECUT2 expression and increased levels other and with noncancerous cells in tumor pathogenesis of stemness-associated genes. These effects following che- and response to therapies. Here, we show that treatment motherapy were diminished in tumors deficient in exosome with a sublethal dose of chemotherapeutic agents induces secretion. In human breast tumors, neoadjuvant chemother-breast cancer cells to secrete EV with the capacity to stim-apy decreased ONECUT2 expression in tumor cells. Our ulate a cancer stem-like cell (CSC) phenotype, rendering results indicate a mechanism by which cancer cells com-cancer cells resistance to therapy. Chemotherapy induced municate with each other and self-adapt to survive in breast cancer cells to secrete multiple EV miRNAs, including response to cytotoxic treatment. Targeting these adaptation miR-9-5p, miR-195-5p, and miR-203a-3p, which simulta-mechanisms along with chemotherapy, such as by blocking neously targeted the transcription factor One Cut Homeo-the EV miRNA–ONECUT2 axis, represents a potential strat-box 2 (ONECUT2), leading to induction of CSC traits egy to maximize the anticancer effect of chemotherapy and and expression of stemness-associated genes, including to reduce chemoresistance in cancer management. NOTCH1, SOX9, NANOG, OCT4, and SOX2. Inhibition of these miRNAs or restoration of ONECUT2 expression abol-Significance: These findings reveal a critical mechanism of ished the CSC-stimulating effect of EV from chemotherapy-resistance to chemotherapy by which breast cancer cells secrete treated cancer cells. In mice bearing xenograft mammary miRNA-containing extracellular vesicles to stimulate cancer tumors, docetaxel treatment caused elevations of miR-9-5p, stem cell-like features.