Journal Article

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

Moyano-Galceran, Lidia, Zhang, Kaiyang, Grénman, Seija, Carlson, Joseph W., Jamalzadeh, Sanaz, Carpén, Olli, Lehtinen, Laura, Gultekin, Okan, Martins, Tomás A., Lehti, Kaisa, Kaipio, Katja, Lamminen, Tarja, Hietanen, Sakari, Joneborg, Ulrika, Lehtonen, Rainer, Hautaniemi, Sampsa, Turunen, S. Pauliina, Pietilä, Elina A., Gonzalez-Molina, Jordi, Hynninen, Johanna

2021

Overview

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. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 14 / 38 / 631/67/327 / 692/4028/67/1517/1709 / 692/4028/67/327 / Adhesion / Antineoplastic Agents - therapeutic use / Apoptosis / Apoptosis - drug effects / Apoptosis - genetics / Cancer / Cell Adhesion - drug effects / Cell Adhesion - genetics / Cell culture / Cell death / Cell Line, Tumor / Chemoresistance / Chemotherapy / Cisplatin - therapeutic use / Coevolution / Collagen / Collagen - genetics / Collagen - metabolism / Crosstalk / Cystadenocarcinoma, Serous - genetics / Cystadenocarcinoma, Serous - metabolism / Cystadenocarcinoma, Serous - pathology / DNA damage / Drug Resistance, Neoplasm - genetics / Evolution / Evolution, Molecular / Extracellular matrix / Extracellular Matrix - drug effects / Extracellular Matrix - metabolism / Female / Fibrosis / Gene Expression Profiling - methods / Gene Expression Regulation, Neoplastic / Heterogeneity / Histology / Humanities and Social Sciences / Humans / Kaplan-Meier Estimate / Metastases / Metastasis / Microenvironments / multidisciplinary / Neoplasm Recurrence, Local / Organoids / Ovarian cancer / Ovarian Neoplasms - genetics / Ovarian Neoplasms - metabolism / Ovarian Neoplasms - pathology / Platinum / Science / Science (multidisciplinary) / Signal Transduction - drug effects / Signal Transduction - genetics / Signaling / Stiffness / Substrates / Transcriptomes / Treatment resistance / Tumor Microenvironment - drug effects / Tumor Microenvironment - genetics / Tumors / Two dimensional models / Yes-associated protein