Extracellular matrix proteins increase invasive growth and chemotherapy resistance of ovarian cancer cells.

Extracellular matrix (ECM) interactions contribute to cancer metastasis and chemotherapy resistance by regulating invasive cancer growth and apoptosis evasion. However, the key ECM pathways activated during cancer evolution, including tumor metastasis and tissue responses to chemotherapy, remain to be systematically identified. Using a unique longitudinal high-grade serous ovarian carcinoma (HGSOC) cohort to understand the ECM deposition and remodeling in response to disease development and chemotherapeutics, we conducted ECM proteome, i.e., matrisome, analysis on HGSOC tissues of distinct anatomic sites from treatment-naive and post-chemotherapy primary samples. Together with an unbiased functional ECM screen for platinum-treatment responses, we report how the solid tumor ECM evolves with disease progression and how specific stromal ECM proteins, including fibronectin, promote ovarian cancer cell motility, invasion, and resistance to platinum treatment. Importantly, we observed these specific stromal ECM proteins to be expressed already at HGSOC omental microlesions with remarkable desmoplastic reaction, as shown by immunohistochemistry of longitudinally collected patient cohort samples. Further, by using clinical The Cancer Genome Atlas (TCGA) microarray data we found that at transcriptional level the overexpression of a specific ECM protein, with platinum-induced cancer cell spreading and migratory response, also associated with poor survival in the treatment-naive TCGA patient data, and was specifically upregulated after chemotherapy in our longitudinal cohort. In ovarian cancer cell cultures and in patient-derived 3D HGSOC organoid cultures, this specific ECM-rich microenvironment associated with an epithelial-to-mesenchymal transition transcriptional markers coupled to a stem-like morphology and properties with increased resistance. These results underline the importance of cell-matrix communication in invasion and chemotherapy response, revealing certain ECM proteins as important promoters of aggressiveness and chemotherapy resistance in the metastatic HGSOC lesions. Citation Format: Elina A. Pietila, Jordi Gonzales-Molina, Lidia Moyano-Galceran, Laura Lehtinen, Pauliina Turunen, Tomas Santos Martins, Ville Rantanen, Antti Hakkinen, Sanaz Jamalzadeh, Kaiyang Zhang, Tarja Lamminen, Katja Kaipio, Johanna Hynninen, Sakari Hietanen, Seija Grenman, Rainer Lehtonen, Sampsa Hautaniemi, Olli Carpen, Kaisa Lehti. Extracellular matrix proteins increase invasive growth and chemotherapy resistance of ovarian cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A64.