Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea; Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea; Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
Department of Biomedical Engineering, Sungkyunkwan University, Suwon, Republic of Korea; School of Mechanical Engineering, Sungkyunkwan University, Suwon, Republic of Korea; Institute of Quantum Biophysics (IQB), Sungkyunkwan University, Suwon, Republic of Korea
Chemoresistance is a major cause of treatment failure in many cancers. However, the life cycle of cancer cells as they respond to and survive environmental and therapeutic stress is understudied. In this study, we utilized a microfluidic device to induce the development of doxorubicin-resistant (DOXR) cells from triple negative breast cancer (TNBC) cells within 11 days by generating gradients of DOX and medium. In vivo chemoresistant xenograft models, an unbiased genome-wide transcriptome analysis, and a patient data/tissue analysis all showed that chemoresistance 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 resistant cells that increase tumor heterogeneity and chemoresistance, highlighting the need for further studies on the epigenetic control of the NUPR1/HDAC11 axis in TNBC.
