Exploration of Mechanisms of Drug Resistance in a Microfluidic Device and Patient Tissues

Author:

Lim Wanyoung1ORCID,Hwang Inwoo2,Zhang Jiande3,Chen Zhenzhong3,Han Jeonghun3ORCID,Jeon Jaehyung3,Koo Bon-Kyoung4ORCID,Kim Sangmin5ORCID,Lee Jeong Eon6ORCID,Kim Youngkwan2,Pienta Kenneth J.7ORCID,Amend Sarah R.7ORCID,Austin Robert H.8ORCID,Ahn Jee-Yin2910ORCID,Park Sungsu1311ORCID

Affiliation:

1. Department of Biomedical Engineering, Sungkyunkwan University

2. Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine

3. School of Mechanical Engineering, Sungkyunkwan University

4. Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC)

5. Department of Breast Cancer Center, Samsung Medical Center, Sungkyunkwan University School of Medicine

6. Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine

7. The Cancer Ecology Center at the James Buchanan Brady Urological Institute, Johns Hopkins School of Medicine

8. Department of Physics, Princeton University

9. Single Cell Network Research Center, Sungkyunkwan University School of Medicine

10. Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine

11. Institute of Quantum Biophysics (IQB), Sungkyunkwan University

Abstract

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.

Publisher

eLife Sciences Publications, Ltd

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