Frizzled-7 Identifies Platinum Tolerant Ovarian Cancer Cells Susceptible to Ferroptosis

Abstract

The authors have no conflicts of interest to declare. AbstractDefining traits of platinum tolerant cancer cells could expose new treatment vulnerabilities. Here, new markers associated with platinum tolerant cells and tumors were identified by using in vitro and in vivo ovarian cancer (OC) models treated repetitively with carboplatin and validated in human specimens. Platinum-tolerant cells and tumors were found to be enriched in ALDH (+) cells, formed more spheroids, and expressed increased levels of stemness-related transcription factors compared to parental cells. Additionally, platinum-tolerant cells and tumors highly expressed the Wnt receptor, Frizzled 7 (FZD7). FZD7 knock down improved sensitivity to platinum, decreased spheroid formation, and delayed tumor initiation. The molecular signature distinguishing FZD7(+) from FZD7(-) cells included epithelial-to-mesenchymal (EMT), stemness, and oxidative phosphorylation enriched gene sets. Overexpression of FZD7 activated the oncogenic factor Tp63, driving upregulation of glutathione metabolism pathways, including glutathione peroxidase 4 (GPX4), which protects cells from chemotherapy-induced oxidative stress. FZD7(+) platinum-tolerant OC cells were more sensitive and underwent ferroptosis after treatment with GPX4 inhibitors. FZD7, Tp63 and glutathione metabolism gene sets were strongly correlated in the OC Tumor Cancer Genome Atlas (TCGA) database and in human OC specimens residual after chemotherapy. These results support the existence of a platinum-tolerant cell population with partial stem cell features, characterized by FZD7 expression and dependent on FZD7-b-catenin-Tp63-GPX4 pathway for survival. The findings reveal a novel therapeutic vulnerability of platinum tolerant cancer cells and provide new insight into a potential "persister cancer cell" phenotype.glutathione peroxidase 4 (GPX4) tumor initiation capacity (TIC) (10). Importantly, ovarian CSCs possess a phenotype associated with drug resistance, including enhanced DNA repair, diminished apoptotic responses, increased efflux mechanisms and enhanced antioxidation defense (8,11), which allow them to escape from chemotherapy. The boundaries between stemness and chemotherapy tolerant phenotypes remain blurry and while an overlap exists, it is assumed that distinct pathways drive the two entities.As platinum tolerant cancer cells drive tumor relapse, decreasing survival rate of women with OC, we aimed to identify specific markers, by using in vitro and in vivo models of repeated exposure to the cytotoxic agent. We observed that platinum-tolerant cells and tumors contained an increased ALDH+ cell population, expressing stemness related transcription factors (TFs), and able to form more spheroids compared to chemotherapy naïve cells. We identified the Frizzled 7 receptor (FZD7) as a novel cell surface marker significantly upregulated in the platinum tolerant cell population. FZD7 knock down increased sensitivity to platinum, decreased spheroid formation in vitro, and delayed tumor initiation in vivo. FZD7...

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A FZD7-specific Antibody–Drug Conjugate Induces Ovarian Tumor Regression in Preclinical Models

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A ferroptosis-related lncRNA signature predicts prognosis in ovarian cancer patients

“…Multiple studies have confirmed that ferroptosis plays an important role in OC. For example, Wang et al reported that platinum-tolerant OC cells are highly susceptible to ferroptosis (17). Furthermore, an overexpressed p53 could contribute to ferroptosis in OC cells (18) and erastin works synergistically with cisplatin to inhibit the growth of OC cell by a ROS-mediated ferroptosis mechanism (19).…”