# ATPase copper transporting beta contributes to cisplatin resistance as a regulatory factor of extracellular vesicles in head and neck squamous cell carcinoma

## TL;DR

This study shows that ATP7B promotes cisplatin resistance in head and neck cancer by regulating extracellular vesicles that spread drug resistance to other cells.

## Contribution

The paper reveals a novel ATP7B–sEV axis that drives chemoresistance in head and neck squamous cell carcinoma.

## Key findings

- ATP7B expression correlates with endocytosis and EMT-related genes and EV-associated proteins in HNSC.
- ATP7B-rich sEVs increase resistance in recipient cells, and their inhibition enhances cisplatin-induced apoptosis.
- Pharmacological inhibition of sEV biogenesis reduces ATP7B and Atox1 expression in xenograft tumors.

## Abstract

Cisplatin (CDDP) resistance remains a major clinical challenge in the treatment of head and neck squamous cell carcinoma (HNSC). Our group identified ATPase copper transporting beta (ATP7B) as a mediator of CDDP resistance through its role in drug efflux and small extracellular vesicle (sEV) secretion. Herein, we uncovered a novel mechanism by which ATP7B regulates sEV dynamics and the intercellular transmission of CDDP resistance. Using transcriptomic analyses of HNSC datasets, we demonstrate that ATP7B expression correlates with endocytosis- and epithelial-mesenchymal transition (EMT)-related gene sets and with elevated levels of EV-associated proteins. CDDP-resistant HNSC cells exhibited upregulated ATP7B, Rab5/Rab7, and preferentially secreted HSP90- and EpCAM-rich sEVs. These sEVs were leading to increased ATP7B expression and reduced CDDP sensitivity in recipient cells. A pharmacological inhibition of sEV biogenesis with GW4869 suppressed ATP7B and Atox1 expressions, inhibited late endosome maturation, and significantly enhanced CDDP-induced apoptosis in HNSC cells. In vivo, GW4869 reduced the sEV protein content and ATP7B expression in xenograft tumors. These findings establish that ATP7B is a critical modulator of sEV cargo and resistance propagation. Our results highlight a previously unrecognized ATP7B–sEV axis driving chemoresistance and identify sEV inhibition as a promising strategy to overcome therapeutic failure in HNSC.