Neutrophils exposed to a cholesterol metabolite secrete extracellular vesicles that promote epithelial-mesenchymal transition and stemness in breast cancer cells.

Natalia Krawczyńska; Yu Wang; Ki Lim; Anasuya Das Gupta; Ralph John Emerson J. Molino; Adam Lenczowski; Marwan Abughazaleh; Shruti V. Bendre; Yifan Fei; Hannah Kim; Lara I. Kockaya; Claire P. Schane; Dhanya Pradeep; Desirée Rodriguez-Casiano; Alvaro Gonzalo Hernandez; Jenny M. Drnevich; Jefferson Chan; Lawrence W. Dobrucki; Marni D. Boppart; Stephanie M. Cologna; Julie Hanson Ostrander; Erik Russell Nelson

doi:10.1016/j.canlet.2025.218105

Cancer BiologyCancer LettersOct 29, 2025

Peer-reviewed journal article

Neutrophils exposed to a cholesterol metabolite secrete extracellular vesicles that promote epithelial-mesenchymal transition and stemness in breast cancer cells.

Natalia Krawczyńska iD, Yu Wang iD, Ki Lim, Anasuya Das Gupta iD, Ralph John Emerson J. Molino iD, Adam Lenczowski iD, Marwan Abughazaleh iD, Shruti V. Bendre iD, Yifan Fei iD, Hannah Kim iD, Lara I. Kockaya iD, Claire P. Schane iD, Dhanya Pradeep iD, Desirée Rodriguez-Casiano iD, Alvaro Gonzalo Hernandez iD, Jenny M. Drnevich iD, Jefferson Chan iD, Lawrence W. Dobrucki iD, Marni D. Boppart iD, Stephanie M. Cologna iD, Julie Hanson Ostrander iD, Erik Russell Nelson iD

Abstract

Small extracellular vesicles (sEVs) are emerging as critical mediators of intercellular communication in the tumor microenvironment (TME). Here, we investigate the mechanisms by which sEVs derived from neutrophils treated with the cholesterol metabolite, 27-hydroxycholesterol (27HC), influence breast cancer progression. sEVs released from 27HC treated neutrophils enhance epithelial-mesenchymal transition (EMT) and stem-like properties in breast cancer cells, resulting in loss of adherence, increased migratory capacity and resistance to cytotoxic chemotherapy. Decreased microRNAs (miRs) within the sEVs resulted in activation of the WNT/{beta}-catenin signaling pathway in recipient cells and suggest that this may be a predominant pathway for stem-like phenotype and EMT. Our findings underscore a novel mechanism by which 27HC-modulated neutrophils contribute to breast cancer pathophysiology through EV-mediated intercellular communication, suggesting potential therapeutic targets in cancer treatment.

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