Drug resistant cancer cells show increased nuclear mechanotransduction and mechanically targetable YAP-regulated vulnerability

Miao Huang; Yinong Chen; Chenyu Liang; Om Prakash Narayan; Chase Stallings; Mu Yu; Conner Traugot; Lu Li; Keming Li; Quang Vo; Heyang Wang; Yu-Ting Chou; Lauren Cech; Daniel Parra; Laura Garzon; Dylan Parsons; Emma Diaz; Cunyu Zhang; Cole Mackey; Hayley Sussman; Izabela Zmirska; Michael Chung; Chen Zhou; Georgios Glynatsis; Dietmar W Siemann; Jonathan D Licht; Chenglong Li; Frederic J Kaye; Mingyi Xie; Youhua Tan; Lizi Wu; Trever G Bivona; Juan Guan; Xin Tang

doi:10.1016/j.biomaterials.2025.123920

Drug resistant cancer cells show increased nuclear mechanotransduction and mechanically targetable YAP-regulated vulnerability

Biomaterials. 2026 Jun:329:123920. doi: 10.1016/j.biomaterials.2025.123920. Epub 2025 Dec 15.

Authors

Miao Huang¹, Yinong Chen², Chenyu Liang¹, Om Prakash Narayan³, Chase Stallings⁴, Mu Yu⁵, Conner Traugot⁶, Lu Li⁶, Keming Li⁷, Quang Vo⁴, Heyang Wang⁸, Yu-Ting Chou⁹, Lauren Cech¹⁰, Daniel Parra¹¹, Laura Garzon¹², Dylan Parsons⁴, Emma Diaz¹³, Cunyu Zhang¹⁴, Cole Mackey¹⁵, Hayley Sussman¹⁶, Izabela Zmirska¹⁷, Michael Chung³, Chen Zhou¹⁸, Georgios Glynatsis¹⁹, Dietmar W Siemann²⁰, Jonathan D Licht²⁰, Chenglong Li¹⁸, Frederic J Kaye²⁰, Mingyi Xie⁶, Youhua Tan¹⁴, Lizi Wu⁵, Trever G Bivona²¹, Juan Guan²², Xin Tang²³

Affiliations

¹ Department of Mechanical and Aerospace Engineering, Herbert Wertheim College of Engineering, University of Florida, Gainesville, FL, 32610, USA; UF Health Cancer Center, University of Florida, Gainesville, FL, 32610, USA.
² Department of Mechanical and Aerospace Engineering, Herbert Wertheim College of Engineering, University of Florida, Gainesville, FL, 32610, USA; UF Health Cancer Center, University of Florida, Gainesville, FL, 32610, USA; J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, 32610, USA.
³ College of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, University of Texas at Austin, Austin, TX, 78712, USA.
⁴ Department of Biology, College of Liberal Arts and Sciences, University of Florida, Gainesville, FL, 32610, USA.
⁵ UF Health Cancer Center, University of Florida, Gainesville, FL, 32610, USA; Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, 32610, USA.
⁶ UF Health Cancer Center, University of Florida, Gainesville, FL, 32610, USA; Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL, USA.
⁷ Mechanobiology Institute, National University of Singapore, Singapore.
⁸ Department of Mechanical Engineering, Robert R. McCormick School of Engineering, Northwestern University, Evanston, IL, USA.
⁹ Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.
¹⁰ Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.
¹¹ Department of Computer & Information Science & Engineering, Herbert Wertheim College of Engineering, University of Florida, Gainesville, FL, 32610, USA.
¹² Department of Mechanical and Aerospace Engineering, Herbert Wertheim College of Engineering, University of Florida, Gainesville, FL, 32610, USA.
¹³ Department of Applied Physiology & Kinesiology, College of Health and Human Performance, University of Florida, Gainesville, FL, 32610, USA.
¹⁴ The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, 518000, China; Research Institute of Smart Ageing, The Hong Kong Polytechnic University, 999077, Hong Kong, China; Department of Biomedical Engineering, The Hong Kong Polytechnic University, 999077, Hong Kong, China.
¹⁵ Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL, USA.
¹⁶ Department of Biomedical Engineering, School of Engineering & School of Medicine, University of Virginia, VA, 22904, USA.
¹⁷ J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, 32610, USA.
¹⁸ Department of Medicinal Chemistry, University of Florida, Gainesville, FL, 32610, USA.
¹⁹ Department of Physics, College of Liberal Arts and Sciences, University of Florida, Gainesville, FL, 32610, USA.
²⁰ Division of Hematology/Oncology, UF Health Cancer Center, University of Florida, Gainesville, FL, 32610, USA.
²¹ Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA; Chan-Zuckerberg Biohub Network, San Francisco, CA, 94158, USA. Electronic address: trever.bivona@ucsf.edu.
²² College of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, University of Texas at Austin, Austin, TX, 78712, USA. Electronic address: juanguan@utexas.edu.
²³ Department of Mechanical and Aerospace Engineering, Herbert Wertheim College of Engineering, University of Florida, Gainesville, FL, 32610, USA; UF Health Cancer Center, University of Florida, Gainesville, FL, 32610, USA; J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, 32610, USA. Electronic address: xin.tang@ufl.edu.

PMID: 41443038
DOI: 10.1016/j.biomaterials.2025.123920

Abstract

Drug resistance is a leading cause of cancer treatment failure and tumor recurrence. Identifying new methods that eliminate life-threatening drug-resistant cancer cells (DRCs) can enhance tumor cell eradication and improve patient outcomes. Here we report that human non-small cell lung cancer (NSCLC) DRCs show previously unrecognized increased sensitivity to mechanical stimuli compared to drug-susceptible lung cancer cells (DSCs) in vitro. Exploiting this heightened mechanical sensitivity, the combination of physiologically soft culture microenvironment with targeted therapies reduces the survival of DRCs through regulating yes-associated-protein (YAP) translocation between nucleus and cytoplasm. Our clinical studies confirm that DRCs possess heightened YAP nuclear localization in both NSCLC patient-derived organoid models and patient tissues, indicating high potential of eradicating DRCs by mechanical stimuli in vivo. Further, our mechanistic analyses, including quantitative imaging, transcriptomic profiling, and pharmacological evaluations reveal that the alterations in nuclear force sensing, rather than actomyosin contractility or Hippo-YAP pathway activation in DRCs, primarily drive the heightened YAP mechanosensitivity. This work highlights the crucial difference in mechanosensitivity between DRCs and DSCs, and points to mechanobiological targeting of these cells as a novel strategy to overcome drug resistance and enhance cancer therapy.

Keywords: CRISPR/Cas9-engineered endogenous protein labelling; Drug resistance; Drug-resistant cancer cells (DRCs); Drug-tolerant persister cells (DTPs); Mechano-targeted cancer vulnerability; Mechanobiology; Nuclear mechanics; Optical interrogation; Yes-associated protein (YAP).

MeSH terms

Adaptor Proteins, Signal Transducing* / metabolism
Carcinoma, Non-Small-Cell Lung* / drug therapy
Carcinoma, Non-Small-Cell Lung* / metabolism
Carcinoma, Non-Small-Cell Lung* / pathology
Cell Line, Tumor
Cell Nucleus* / drug effects
Cell Nucleus* / metabolism
Drug Resistance, Neoplasm*
Humans
Lung Neoplasms* / drug therapy
Lung Neoplasms* / metabolism
Lung Neoplasms* / pathology
Mechanotransduction, Cellular* / drug effects
Transcription Factors* / metabolism
YAP-Signaling Proteins

Substances

YAP-Signaling Proteins
Adaptor Proteins, Signal Transducing
YAP1 protein, human
Transcription Factors