Dormancy-inducing 3D-engineered matrix uncovers mechanosensitive and drug protective FHL2-p21 signaling axis

  1. Bakhshandeh, Sadra 1
  2. Heras Manterola, Unai 23
  3. Taïeb, Dr. Hubert Mordehaï 1
  4. Varadarajan, Adithi Ravikumar 4
  5. Lissek, Susanna M. 5
  6. Hücker, Sarah 4
  7. Lu, Xin 4
  8. Garske, Daniela 1
  9. Young, Sarah A. E. 1
  10. Abaurrea, Andrea 2
  11. Caffarel, Maria 26
  12. Riestra, Ana Cristina 78
  13. Bragado Domingo, Paloma 910
  14. Contzen, Jörg 111213
  15. Gossen, Manfred 12
  16. Kirsch, Stefan 4
  17. Warfsmann, Jens 4
  18. Honarnejad, Kamran 4
  19. Klein, Christoph A. 45
  20. Cipitria, Dr. Amaia 11415
  1. 1 Max Planck Institute of Colloids and Interfaces
    info

    Max Planck Institute of Colloids and Interfaces

    Potsdam, Alemania

    ROR https://ror.org/00pwgnh47

  2. 2 Instituto de Investigación Sanitaria Biogipuzkoa
    info

    Instituto de Investigación Sanitaria Biogipuzkoa

    San Sebastián, España

    ROR 01a2wsa50

  3. 3 Universidad del País Vasco/Euskal Herriko Unibertsitatea
    info

    Universidad del País Vasco/Euskal Herriko Unibertsitatea

    Lejona, España

    ROR https://ror.org/000xsnr85

  4. 4 Fraunhofer Institute for Toxicology and Experimental Medicine
    info

    Fraunhofer Institute for Toxicology and Experimental Medicine

    Hanóver, Alemania

    ROR https://ror.org/02byjcr11

  5. 5 University of Regensburg
    info

    University of Regensburg

    Ratisbona, Alemania

    ROR https://ror.org/01eezs655

  6. 6 Ikerbasque
  7. 7 Fundación Onkologikoa Fundazioa
  8. 8 Universidad de Deusto
    info

    Universidad de Deusto

    Bilbao, España

    ROR https://ror.org/00ne6sr39

  9. 9 Universidad Complutense de Madrid
    info

    Universidad Complutense de Madrid

    Madrid, España

    ROR 02p0gd045

  10. 10 Hospital Clínico San Carlos de Madrid
    info

    Hospital Clínico San Carlos de Madrid

    Madrid, España

    ROR https://ror.org/04d0ybj29

  11. 11 Charité - Universitätsmedizin Berlin
  12. 12 Helmholtz-Zentrum Hereon
  13. 13 Berlin-Brandenburger Centrum für Regenerative Therapien
  14. 14 Biodonostia Health Research Institute San Sebastian
  15. 15 Basque Foundation for Science Bilbao
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Verleger: Edmond

Datum der Publikation: 2024

Art: Dataset

DOI: 10.17617/3.PWPUU0 lock_openOpen Access editor

Zusammenfassung

Resected tumors frequently relapse with distant metastasis, despite systemic treatment. Cellular dormancy has been identified as an important mechanism underlying such drug resistance enabling late relapse. Nonetheless, hurdles associated with detection and isolation of disseminated cancer cells (DCCs) in disease-free patients urge the need for in vitro models of dormant cells suited for drug discovery. Here, we explore dormancy-inducing 3D-engineered matrices, which generate mechanical confinement and induce growth arrest and survival against chemotherapy in cancer cells. We characterized the dormant phenotype of solitary cells by P-ERKlow:P-p38high dormancy signaling ratio, along with Ki67- expression. As underlying mechanism, we identified stiffness-dependent nuclear localization of the four-and-a-half LIM domains 2 (FHL2) protein, leading to p53-independent high p21Cip1/Waf1 nuclear expression, validated in murine and human tissue. Suggestive of a resistance-causing role, cells in the dormancy-inducing matrix became sensitive against chemotherapy upon FHL2 downregulation. Thus, our biomaterial-based approach will enable systematic screens for novel compounds suited to eradicate potentially relapsing, dormant cancer cells.