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Co-evolution of matrisome and adaptive adhesion dynamics drives ovarian cancer chemoresistance

Author

Listed:
  • Elina A. Pietilä

    (University of Helsinki)

  • Jordi Gonzalez-Molina

    (Karolinska Institutet
    Karolinska Institutet)

  • Lidia Moyano-Galceran

    (Karolinska Institutet)

  • Sanaz Jamalzadeh

    (University of Helsinki)

  • Kaiyang Zhang

    (University of Helsinki)

  • Laura Lehtinen

    (University of Turku)

  • S. Pauliina Turunen

    (Karolinska Institutet)

  • Tomás A. Martins

    (University of Helsinki)

  • Okan Gultekin

    (Karolinska Institutet
    Karolinska Institutet)

  • Tarja Lamminen

    (University of Turku)

  • Katja Kaipio

    (University of Turku)

  • Ulrika Joneborg

    (Karolinska Institutet
    Karolinska University Hospital)

  • Johanna Hynninen

    (Turku University Hospital, University of Turku)

  • Sakari Hietanen

    (Turku University Hospital, University of Turku)

  • Seija Grénman

    (Turku University Hospital, University of Turku)

  • Rainer Lehtonen

    (University of Helsinki)

  • Sampsa Hautaniemi

    (University of Helsinki)

  • Olli Carpén

    (University of Helsinki
    University of Turku
    Helsinki University Hospital)

  • Joseph W. Carlson

    (Karolinska Institutet)

  • Kaisa Lehti

    (University of Helsinki
    Karolinska Institutet
    Norwegian University of Science and Technology)

Abstract

Due to its dynamic nature, the evolution of cancer cell-extracellular matrix (ECM) crosstalk, critically affecting metastasis and treatment resistance, remains elusive. Our results show that platinum-chemotherapy itself enhances resistance by progressively changing the cancer cell-intrinsic adhesion signaling and cell-surrounding ECM. Examining ovarian high-grade serous carcinoma (HGSC) transcriptome and histology, we describe the fibrotic ECM heterogeneity at primary tumors and distinct metastatic sites, prior and after chemotherapy. Using cell models from systematic ECM screen to collagen-based 2D and 3D cultures, we demonstrate that both specific ECM substrates and stiffness increase resistance to platinum-mediated, apoptosis-inducing DNA damage via FAK and β1 integrin-pMLC-YAP signaling. Among such substrates around metastatic HGSCs, COL6 was upregulated by chemotherapy and enhanced the resistance of relapse, but not treatment-naïve, HGSC organoids. These results identify matrix adhesion as an adaptive response, driving HGSC aggressiveness via co-evolving ECM composition and sensing, suggesting stromal and tumor strategies for ECM pathway targeting.

Suggested Citation

  • Elina A. Pietilä & Jordi Gonzalez-Molina & Lidia Moyano-Galceran & Sanaz Jamalzadeh & Kaiyang Zhang & Laura Lehtinen & S. Pauliina Turunen & Tomás A. Martins & Okan Gultekin & Tarja Lamminen & Katja K, 2021. "Co-evolution of matrisome and adaptive adhesion dynamics drives ovarian cancer chemoresistance," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24009-8
    DOI: 10.1038/s41467-021-24009-8
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