Exploration of mechanisms of drug resistance by polyaneuploid cancer cells in a microfluidic device and patient tissues

Chemoresistance can be increased by cells in the polyaneuploid cancer cells (PACC) state, a major cause of treatment failure in various cancers. The life cycle of cells in the PACC state is understudied, and the mechanism of their drug resistance is unknown. In this study, we induced the development of doxorubicin (DOX)-resistant PACCs from triple negative breast cancer (TNBC) cells within 11 days using a microfluidic device that generates a DOX concentration gradient. In vivo chemoresistant xenograft models, an unbiased genome-wide transcriptome analysis, and a patient data/tissue analysis all showed that chemoresistance of the PACCs arose from failed epigenetic control of the nuclear protein 1 (NUPR1)/histone deacetylase 11 (HDAC11) axis, and high Nupr1 expression correlated with poor clinical outcomes. These results suggest that the chip can rapidly induce clinically relevant PACCs, and that cells in the PACC state increase tumor heterogeneity and chemoresistance. ### Competing Interest Statement The authors have declared no competing interest.