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

Miao Huang1, Yinong Chen2, Chenyu Liang1

  • 1Department 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.

Biomaterials
|December 24, 2025
PubMed

Insights

Drug-resistant lung cancer cells are more sensitive to mechanical forces. Targeting this mechanosensitivity, particularly YAP nuclear localization, offers a new strategy to eliminate resistant cancer cells and improve treatment outcomes.

Area of Science:

  • Oncology
  • Mechanobiology
  • Biophysics

Background:

  • Drug resistance is a major challenge in cancer therapy, leading to treatment failure and recurrence.
  • Developing novel strategies to eliminate drug-resistant cancer cells (DRCs) is crucial for improving patient outcomes.
  • Non-small cell lung cancer (NSCLC) is a significant cause of cancer-related mortality.

Purpose of the Study:

  • To investigate the mechanical sensitivity of drug-resistant NSCLC cells.
  • To explore novel therapeutic strategies targeting the unique properties of DRCs.
  • To elucidate the mechanisms underlying the heightened mechanosensitivity of DRCs.

Main Methods:

  • In vitro mechanical stimulation assays comparing drug-resistant cancer cells (DRCs) and drug-susceptible cancer cells (DSCs).
  • Quantitative imaging, transcriptomic profiling, and pharmacological evaluations to analyze cellular responses.
  • Analysis of YAP (Yes-associated protein) translocation and nuclear localization in response to mechanical stimuli.
  • In vivo studies using NSCLC patient-derived organoid models and patient tissues.

Main Results:

  • DRCs exhibit significantly increased sensitivity to mechanical stimuli compared to DSCs.
  • A soft culture microenvironment combined with targeted therapies reduces DRC survival by modulating YAP translocation.
  • DRCs show heightened YAP nuclear localization in patient-derived organoids and tissues.
  • Alterations in nuclear force sensing, not actomyosin contractility or Hippo-YAP pathway activation, drive YAP mechanosensitivity in DRCs.

Conclusions:

  • Drug-resistant NSCLC cells possess a unique mechanosensitivity that can be therapeutically exploited.
  • Targeting YAP mechanosensitivity presents a promising novel strategy to overcome drug resistance in NSCLC.
  • This research opens new avenues for mechanobiological interventions in cancer therapy.
Keywords:
CRISPR/Cas9-engineered endogenous protein labellingDrug resistanceDrug-resistant cancer cells (DRCs)Drug-tolerant persister cells (DTPs)Mechano-targeted cancer vulnerabilityMechanobiologyNuclear mechanicsOptical interrogationYes-associated protein (YAP)

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