Abstract
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 in vitro and in vivo ovarian cancer models treated repetitively with carboplatin and validated in human specimens. Platinum-tolerant cells and tumors were enriched in ALDHþ 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 Frizzled-7 (FZD7). Knockdown of FZD7 improved sensitivity to platinum, decreased spheroid formation, and delayed tumor initiation. The molecular signature distinguishing FZD7þ 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 protected cells from chemotherapy-induced oxidative stress. FZD7þ platinum-tolerant ovarian cancer cells were more sensitive and underwent ferroptosis after treatment with GPX4 inhibitors. FZD7, Tp63, 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–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. 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 384-399 |
| Number of pages | 16 |
| Journal | Cancer Research |
| Volume | 81 |
| Issue number | 2 |
| DOIs | |
| State | Published - Jan 15 2021 |
Funding
E. Tanner reports personal fees from Merck and AstraZeneca outside the submitted work. R.V. Davuluri reports grants from National Library of Medicine during the conduct of the study. D. Matei reports grants from NCI and OCRA during the conduct of the study; personal fees from Astra Zenecca, GSK, Clovis, and Gynecologic Oncology Foundation outside the submitted work. No disclosures were reported by the other authors. This research was supported by funding from the Ovarian Cancer Research Alliance, the NCI (R01-CA224275), and the Diana Princess of Wales endowed Professorship from the Lurie Cancer Center to D. Matei and Friends of Prentice Award to S. Condello and D Matei. Tumor specimens were procured through the Tissue Pathology Core, and sequencing was performed in the NUSeq Core supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. Flow cytometry analyses were performed in the Northwestern University– Flow Cytometry Core Facility supported by Cancer Center Support Grant NCI CA060553. This research was supported in part through the computational resources and staff contributions provided for the Quest high-performance computing facility at Northwestern University, which is jointly supported by the Office of the Provost, the Office for Research, and Northwestern University Information Technology. This research was supported by funding from the Ovarian Cancer Research Alliance, the NCI (R01-CA224275), and the Diana Princess of Wales endowed Professorship from the Lurie Cancer Center to D. Matei and Friends of Prentice Award to S. Condello and D Matei. Tumor specimens were procured through the Tissue Pathology Core, and sequencing was performed in the NUSeq Core supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. Flow cytometry analyses were performed in the Northwestern University?Flow Cytometry Core Facility supported by Cancer Center Support Grant NCI CA060553. This research was supported in part through the computational resources and staff contributions provided for the Quest high-performance computing facility at Northwestern University, which is jointly supported by the Office of the Provost, the Office for Research, and Northwestern University Information Technology.
ASJC Scopus subject areas
- Oncology
- Cancer Research
