Defining 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-beta-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.

中文翻译：

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Frizzled-7鉴定易受Ferroptosis感染的铂耐受性卵巢癌细胞

定义铂耐受性癌细胞的特征可能会暴露出新的治疗漏洞。在这里，通过使用经卡铂反复治疗并在人体标本中验证过的体外和体内卵巢癌（OC）模型，鉴定了与铂耐受细胞和肿瘤相关的新标记。与亲代细胞相比，发现耐铂的细胞和肿瘤富含ALDH（+）细胞，形成更多的球状体，并且表达的干性相关转录因子水平增加。此外，铂耐受细胞和肿瘤高表达Wnt受体，卷曲的7（FZD7）。FZD7降低了对铂的敏感性，减少了球状体的形成，并延迟了肿瘤的发生。将FZD7（+）与FZD7（-）细胞区分开的分子标记包括上皮到间充质（EMT），干性，和氧化磷酸化富集的基因集。FZD7的过度表达激活了致癌因子Tp63，从而驱动了谷胱甘肽代谢途径（包括谷胱甘肽过氧化物酶4（GPX4））的上调，从而保护细胞免受化学疗法诱导的氧化应激。FZD7（+）铂耐受性OC细胞更敏感，并在用GPX4抑制剂治疗后发生了肥大病。FZD7，Tp63和谷胱甘肽代谢基因组在OC肿瘤基因组图谱（TCGA）数据库中和化疗后残留的人OC标本中密切相关。这些结果支持存在具有部分干细胞特征的铂耐受细胞群，其特征在于FZD7表达并依赖于FZD7-β-catenin-Tp63-GPX4存活途径。