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ATRA mechanically reprograms pancreatic stellate cells to suppress matrix remodelling and inhibit cancer cell invasion

Author

Listed:
  • Antonios Chronopoulos

    (Cellular and Molecular Biomechanics Laboratory, Imperial College London)

  • Benjamin Robinson

    (Cellular and Molecular Biomechanics Laboratory, Imperial College London)

  • Muge Sarper

    (Cellular and Molecular Biomechanics Laboratory, Imperial College London)

  • Ernesto Cortes

    (Cellular and Molecular Biomechanics Laboratory, Imperial College London)

  • Vera Auernheimer

    (Biophysics Group, University of Erlangen-Nuremberg)

  • Dariusz Lachowski

    (Cellular and Molecular Biomechanics Laboratory, Imperial College London)

  • Simon Attwood

    (Cellular and Molecular Biomechanics Laboratory, Imperial College London)

  • Rebeca García

    (Cellular and Molecular Biomechanics Laboratory, Imperial College London)

  • Saba Ghassemi

    (University of Pennsylvania School of Medicine)

  • Ben Fabry

    (Biophysics Group, University of Erlangen-Nuremberg)

  • Armando del Río Hernández

    (Cellular and Molecular Biomechanics Laboratory, Imperial College London)

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a dismal survival rate. Persistent activation of pancreatic stellate cells (PSCs) can perturb the biomechanical homoeostasis of the tumour microenvironment to favour cancer cell invasion. Here we report that ATRA, an active metabolite of vitamin A, restores mechanical quiescence in PSCs via a mechanism involving a retinoic acid receptor beta (RAR-β)-dependent downregulation of actomyosin (MLC-2) contractility. We show that ATRA reduces the ability of PSCs to generate high traction forces and adapt to extracellular mechanical cues (mechanosensing), as well as suppresses force-mediated extracellular matrix remodelling to inhibit local cancer cell invasion in 3D organotypic models. Our findings implicate a RAR-β/MLC-2 pathway in peritumoural stromal remodelling and mechanosensory-driven activation of PSCs, and further suggest that mechanical reprogramming of PSCs with retinoic acid derivatives might be a viable alternative to stromal ablation strategies for the treatment of PDAC.

Suggested Citation

  • Antonios Chronopoulos & Benjamin Robinson & Muge Sarper & Ernesto Cortes & Vera Auernheimer & Dariusz Lachowski & Simon Attwood & Rebeca García & Saba Ghassemi & Ben Fabry & Armando del Río Hernández, 2016. "ATRA mechanically reprograms pancreatic stellate cells to suppress matrix remodelling and inhibit cancer cell invasion," Nature Communications, Nature, vol. 7(1), pages 1-12, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12630
    DOI: 10.1038/ncomms12630
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    Cited by:

    1. Jinglin Zou & Cong Jiang & Qiangsheng Hu & Xinlin Jia & Shuqi Wang & Shiyue Wan & Yuanqing Mao & Dapeng Zhang & Peng Zhang & Bin Dai & Yongsheng Li, 2025. "Tumor microenvironment-responsive engineered hybrid nanomedicine for photodynamic-immunotherapy via multi-pronged amplification of reactive oxygen species," Nature Communications, Nature, vol. 16(1), pages 1-16, December.

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