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

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 Kaipio, Ulrika Joneborg, Johanna Hynninen, Sakari Hietanen, Seija Grénman, Rainer Lehtonen, Sampsa Hautaniemi, Olli Carpén, Joseph W. Carlson and Kaisa Lehti ()
Additional contact information
Elina A. Pietilä: University of Helsinki
Jordi Gonzalez-Molina: 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
Tarja Lamminen: University of Turku
Katja Kaipio: University of Turku
Ulrika Joneborg: Karolinska Institutet
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
Joseph W. Carlson: Karolinska Institutet
Kaisa Lehti: University of Helsinki

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24009-8

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