Exploration of drug resistance mechanisms in triple negative breast cancer cells using a microfluidic device and patient tissues

Sep 21, 2026

Chemoresistance is a major cause of cancer treatment failure, yet how cancer cells respond to and survive environmental and therapeutic stress remains insufficiently characterized. This study uses a microfluidic device to generate doxorubicin-resistant (DOXR) cells from triple negative breast cancer (TNBC) cells within 11 days by creating gradients of DOX and medium. In vivo chemoresistant xenografts, genome-wide transcriptomics, and patient tissue analyses indicate chemoresistance results from failed epigenetic control of the NUPR1/HDAC11 axis, with high NUPR1 predicting poor clinical outcomes. The microfluidic approach rapidly induces resistant cells that may enhance tumor heterogeneity and chemoresistance, supporting further study of NUPR1/HDAC11 epigenetic regulation in TNBC.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages18

Reading Time45 min

AccessFree to download

Introduction

Microfluidic chips for studying drug resistance

Purpose and approach of the study

RESEARCH ARTICLE *For correspondence: [jeeahn@skku.edu](jeeahn@skku.edu) (JYA); [nanopark@skku.edu](nanopark@skku.edu) (SP) †These authors contributed equally to this work Competing interest: The authors declare that no competing interests exist. Funding: See page 14 Sent for Review 09 May 2023 Preprint posted 24 May 2023 Reviewed preprint posted 03 October 2023 Reviewed preprint revised 28 February 2024 Version of Record published 27 March 2024 Reviewing Editor: Goutham Narla, University of Michigan– Ann Arbor, United States Copyright Lim, Hwanget al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Exploration of drug resistance mechanisms in triple negative breast cancer cells using a microfluidic device and patient tissues Wanyoung Lim1†, Inwoo Hwang2†, Jiande Zhang3, Zhenzhong Chen3, Jeonghun Han3, Jaehyung Jeon3, Bon-Kyoung Koo4, Sangmin Kim5, Jeong Eon Lee6, Youngkwan Kim2, Kenneth J Pienta7, Sarah R Amend7, Robert H Austin8, Jee-Yin Ahn2,9,10*, Sungsu Park1,3,11* 1 Department of Biomedical Engineering, Sungkyunkwan University, Suwon, Republic of Korea; 2 Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea; 3School of Mechanical Engineering, Sungkyunkwan University, Suwon, Republic of Korea; 4 Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Vienna, Austria; 5 Department of Breast Cancer Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 6 Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 7The Cancer Ecology Center at the James Buchanan Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, United States; 8 Department of Physics, Princeton University, Princeton, United States; 9Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea; 10Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 11 Institute of Quantum Biophysics (IQB), Sungkyunkwan University, Suwon, Republic of Korea 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. eLife assessment This study based on the use of Cancer Drug Resistance Accelerator (CDRA) chip is valuable as a platform technology to assess chemoresistance mechanisms. The strength is convincing from the technological point of view. However, the use of a single cell line model is a limitation. However we Lim, Hwang et al. eLife 2023;12:RP88830. DOI: [https://doi.org/10.7554/eLife.88830](https://doi.org/10.7554/eLife.88830) 1 of 18 Research article Cancer Biology acknowledge the authors' plan to further validate their current findings across multiple TNBC cell lines. Introduction A

FAQs

How were doxorubicin-resistant TNBC cells generated in this research?

A Cancer Drug Resistance Accelerator (CDRA) microfluidic chip was used to create gradients of doxorubicin (DOX) and medium, inducing DOX-resistant (DOXR) cells from MDA-MB-231 TNBC cells within 11 days.

What molecular mechanism was implicated in chemoresistance?

Chemoresistance was linked to failed epigenetic control of the NUPR1/HDAC11 axis, and elevated NUPR1 expression correlated with poor clinical outcomes.

What evidence supported the conclusions beyond cell-based experiments?

The study reports supporting findings from in vivo chemoresistant xenograft models, unbiased genome-wide transcriptome analysis, and patient tissue/data analyses.

Sep 21, 2026

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