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

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Pietilä , E A , Gonzalez-Molina , J , Moyano-Galceran , L , Jamalzadeh , S , Zhang , K , Lehtinen , L , Turunen , S P , Martins , T A , Gultekin , O , Lamminen , T , Kaipio , K , Joneborg , U , Hynninen , J , Hietanen , S , Grenman , S , Lehtonen , R , Hautaniemi , S , Carpen , O , Carlson , J W & Lehti , K 2021 , ' Co-evolution of matrisome and adaptive adhesion dynamics drives ovarian cancer chemoresistance ' , Nature Communications , vol. 12 , no. 1 , 3904 .

Title: Co-evolution of matrisome and adaptive adhesion dynamics drives ovarian cancer chemoresistance
Author: Pietilä, Elina A.; Gonzalez-Molina, Jordi; Moyano-Galceran, Lidia; Jamalzadeh, Sanaz; Zhang, Kaiyang; Lehtinen, Laura; Turunen, S. Pauliina; Martins, Tomas A.; Gultekin, Okan; Lamminen, Tarja; Kaipio, Katja; Joneborg, Ulrika; Hynninen, Johanna; Hietanen, Sakari; Grenman, Seija; Lehtonen, Rainer; Hautaniemi, Sampsa; Carpen, Olli; Carlson, Joseph W.; Lehti, Kaisa
Contributor organization: Research Program in Systems Oncology
Kaisa Irene Lehti / Principal Investigator
INDIVIDRUG - Individualized Drug Therapy
Sampsa Hautaniemi / Principal Investigator
Research Programs Unit
Faculty Common Matters (Faculty of Medicine)
Department of Biochemistry and Developmental Biology
Precision Cancer Pathology
Department of Pathology
Olli Mikael Carpen / Principal Investigator
Date: 2021-06-23
Language: eng
Number of pages: 19
Belongs to series: Nature Communications
ISSN: 2041-1723
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 beta 1 integrin-pMLC-YAP signaling. Among such substrates around metastatic HGSCs, COL6 was upregulated by chemotherapy and enhanced the resistance of relapse, but not treatment-naive, 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. Platinum chemotherapy is standard of care in ovarian cancers but treatment resistance commonly develops. Here, the authors show that the extracellular microenvironment is modulated following chemotherapy and the changes in matrix proteins and stiffness alter the cell death response of tumour cells.
3122 Cancers
3123 Gynaecology and paediatrics
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion

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