Cancer Associated Fibroblasts Provide a Cancer Stem Cell Niche that Leads to Disease Relapse in Ovarian Cancer

ISBN-10
ISBN-13
9798379735913
Category
Biochemistry
Language
English
Published
2023
Author
Yiming Fang

Description

Epithelial ovarian cancer is the most lethal gynecologic malignancy with a 5-year survival rate of only 48%. While most ovarian cancer patients respond to chemotherapy initially, frequent relapse (~80%) and development of chemoresistance result in poor patient outcomes. Cancer stem cells (CSCs) consist of a small subpopulation in the tumor that are capable of surviving from chemotherapy and causing tumor relapse. Using patient specimens and in vitro models, we determined that CSCs are enriched by cancer associated fibroblasts (CAFs) after chemotherapy. Cancer associated fibroblasts (CAFs) are a major constituent of the ovarian cancer tumor microenvironment and are highly enriched in the residual tumors following chemotherapy. Therefore, we studied the mechanism by which CAFs promote ovarian cancer chemoresistance and disease relapse. CAFs isolated from ovarian cancer patient tumors were used in heterotypic 2D or 3D coculture systems with high-grade serous ovarian cancer cell lines or with patient-derived ovarian cancer cells to study their effect on CSCs and chemoresistance. Matched pre-and post-chemotherapy patient tumors were used to confirm our findings. CAFs significantly increased adjacent cancer cell resistance to carboplatin by enriching CSCs. Pre-coculture with CAFs increased in vivo tumor initiation capacity of the ovarian cancer cells by 10-fold in limiting dilution assay analysis (ELDA) in mice. The CSC-CAF crosstalk responsible for CSC induction was found to be mediated by Wnt5a signaling. CRISPR knockdown of Wnt5a in CAFs or treatment with a specific Wnt5a inhibitor abrogated the induction of CSCs by CAFs. Only cancer cells with ROR2, a Wnt coreceptor, respond to Wnt5a signaling triggered by CAFs and developed into CSCs. Responders were found to signal through a non-canonical Wnt pathway involving the coreceptor ROR2, protein kinase C (PKC), and cAMP Responsive Element Binding Protein 1 (CREB1). Inhibition of each of them prevented CSC induction and functional rescue experiments were performed to confirm the sequence of the Wnt5a-ROR2-PKC-CREB1 axis. Treatment of mouse xenografts, established by co-injection of CAFs and ovarian cancer cells, with the Wnt5a inhibitor sensitized them to carboplatin, and eliminated the CSCs in the residual tumors. Our results indicate that CAF-derived Wnt5a is instrumental in ovarian cancer CSC growth and maintenance. Targeting Wnt5a in tumor effectively prevents tumor relapse after cytotoxic chemotherapy by destroying suitable CSC-enriching microenvironment. In the long term, our studies will broaden the understanding of the mechanism of CSC maintenance by the tumor microenvironment and contribute towards the development of novel therapeutic approaches to prevent ovarian cancer chemoresistance and relapse.

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