Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, Indiana.
Cancer Res. 2021 Jan 15;81(2):384-399. doi: 10.1158/0008-5472.CAN-20-1488. Epub 2020 Nov 10.
Defining traits of platinum-tolerant cancer cells could expose new treatment vulnerabilities. Here, new markers associated with platinum-tolerant cells and tumors were identified using and ovarian cancer models treated repetitively with carboplatin and validated in human specimens. Platinum-tolerant cells and tumors were enriched in ALDH cells, formed more spheroids, and expressed increased levels of stemness-related transcription factors compared with parental cells. Additionally, platinum-tolerant cells and tumors exhibited expression of the Wnt receptor (). Knockdown of FZD7 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 , driving upregulation of glutathione metabolism pathways, including glutathione peroxidase 4 (GPX4), which protected cells from chemotherapy-induced oxidative stress. FZD7 platinum-tolerant ovarian cancer cells were more sensitive and underwent ferroptosis after treatment with GPX4 inhibitors. , and glutathione metabolism gene sets were strongly correlated in the ovarian cancer Tumor Cancer Genome Atlas (TCGA) database and in residual human ovarian cancer specimens after chemotherapy. These results support the existence of a platinum-tolerant cell population with partial cancer stem cell features, characterized by FZD7 expression and dependent on the FZD7-β-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. SIGNIFICANCE: Frizzled-7 marks platinum-tolerant cancer cells harboring stemness features and altered glutathione metabolism that depend on GPX4 for survival and are highly susceptible to ferroptosis.
鉴定耐铂癌细胞的特征可能揭示新的治疗弱点。在这里，使用和卵巢癌模型，通过重复用卡铂处理，并在人类标本中验证，鉴定出与耐铂细胞和肿瘤相关的新标志物。与亲本细胞相比，耐铂细胞和肿瘤在 ALDH 细胞中富集，形成更多的球体，并表达更高水平的与干性相关的转录因子。此外，耐铂细胞和肿瘤表现出 Wnt 受体 () 的表达。FZD7 的敲低提高了对铂的敏感性，减少了球体的形成，并延迟了肿瘤的起始。将 FZD7 与 FZD7 细胞区分开来的分子特征包括上皮间质转化 (EMT)、干性和氧化磷酸化富集的基因集。FZD7 的过表达激活了致癌因子，上调了谷胱甘肽代谢途径，包括谷胱甘肽过氧化物酶 4 (GPX4)，这保护细胞免受化疗引起的氧化应激。FZD7 耐铂卵巢癌细胞在接受 GPX4 抑制剂治疗后对铁死亡更敏感，并经历铁死亡。此外，卵巢癌肿瘤癌症基因组图谱 (TCGA) 数据库和化疗后残留的人类卵巢癌标本中，谷胱甘肽代谢基因集强烈相关。这些结果支持存在具有部分癌症干细胞特征的耐铂细胞群，其特征是 FZD7 表达，并依赖 FZD7-β-catenin-Tp63-GPX4 途径生存。这些发现揭示了耐铂癌细胞的新治疗弱点，并为潜在的“持久癌细胞”表型提供了新的见解。意义：卷曲蛋白 7 标记具有干性特征和改变的谷胱甘肽代谢的耐铂癌细胞，这些细胞依赖 GPX4 生存，对铁死亡高度敏感。
