Constructing a co-culture model of cancer-associated fibroblasts and ovarian cancer organoids and studying mechanisms of drug resistance

Abstract

Background: Drug resistance contributes to the relatively low 5-year survival rate in ovarian cancer patients. Due to the complex cell-cell interactions in the tumor microenvironment, the mechanism of drug resistance is highly intricate. Here, we aim to establish 3-dimensional (3D) organotypic co-cultures of primary ovarian cancer-derived organoids with cancer-associated fibroblasts (CAFs) and to understand their interactions and the response to treatment.

Methods: CAFs and organoids were isolated from tissues of a patient with high-grade serous ovarian cancer, and a 3D co-culture model of organoids with CAFs was established in vitro. The organoid growth and drug sensitivity were compared with and without the presence of CAFs. Gene expression analysis was conducted to identify the key genes and pathways leading to the phenotypic changes.

Results: We successfully constructed a 3D co-culture model of human ovarian cancer organoids with CAFs. CAFs have been observed to promote organoids growth and protect them from paclitaxel and cisplatin treatment. Transcriptome analysis suggested that CAFs may mediate organoid growth and promote resistance through multiple pathways, including the PI3K-Akt signaling pathway and cytokine-cytokine receptor interaction. Additionally, patients with high ovarian CAF signature exhibited a poor prognosis in three public ovarian cancer cohorts.

Conclusion: In conclusion, this study demonstrates that the integration of CAFs into an ovarian cancer organoid culture model results in the promotion of tumor growth and the mediation of resistance through multiple signaling pathways. This provides a reliable research model for elucidating the mechanisms underlying drug resistance in ovarian cancer and the development of targeted therapies.

Keywords: Cancer-associated fibroblasts (CAFs); Co-culture; Drug resistance; Organoids; Ovarian cancer.