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

Published on May 30, 2020in bioRxiv
· DOI :10.1101/2020.05.28.121590
Yinu Wang8
Estimated H-index: 8
(NU: Northwestern University),
Yinu Wang4
Estimated H-index: 4
(NU: Northwestern University)
+ 10 AuthorsDaniela Matei2
Estimated H-index: 2
(NU: Northwestern University)
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.
📖 Papers frequently viewed together
2 Citations
15 Citations
#1Mary Goldman (UCSC: University of California, Santa Cruz)H-Index: 20
#2Brian Craft (UCSC: University of California, Santa Cruz)H-Index: 19
Last. David Haussler (UCSC: University of California, Santa Cruz)H-Index: 177
view all 12 authors...
UCSC Xena is a visual exploration resource for both public and private omics data, supported through the web-based Xena Browser and multiple turn-key Xena Hubs. This unique archecture allows researchers to view their own data securely, using private Xena Hubs, simultaneously visualizing large public cancer genomics datasets, including TCGA and the GDC. Data integration occurs only within the Xena Browser, keeping private data private. Xena supports virtually any functional genomics data, includi...
233 CitationsSource
#1Giovanni C. Forcina (Stanford University)H-Index: 6
#2Scott J. Dixon (Stanford University)H-Index: 31
: Oxygen is necessary for aerobic metabolism but can cause the harmful oxidation of lipids and other macromolecules. Oxidation of cholesterol and phospholipids containing polyunsaturated fatty acyl chains can lead to lipid peroxidation, membrane damage, and cell death. Lipid hydroperoxides are key intermediates in the process of lipid peroxidation. The lipid hydroperoxidase glutathione peroxidase 4 (GPX4) converts lipid hydroperoxides to lipid alcohols, and this process prevents the iron (Fe2+ )...
69 CitationsSource
#1Kunihiko Hinohara (Harvard University)H-Index: 20
#2Kornelia Polyak (Harvard University)H-Index: 108
Most human tumors are composed of genetically and phenotypically heterogeneous cancer cell populations, which poses a major challenge for the clinical management of cancer patients. Advances of single-cell technologies have allowed the profiling of tumors at unprecedented depth, which, in combination with newly developed computational tools, enable the dissection of tumor evolution with increasing precision. However, our understanding of mechanisms that regulate intratumoral heterogeneity and ou...
61 CitationsSource
#1Takeshi Fukumoto (Wistar Institute)H-Index: 21
#1Takeshi Fukumoto (Wistar Institute)H-Index: 11
Last. Rugang Zhang (Wistar Institute)H-Index: 42
view all 12 authors...
Despite the high initial response rates to PARP inhibitors (PARPi) in BRCA-mutated epithelial ovarian cancers (EOC), PARPi resistance remains a major challenge. Chemical modifications of RNAs have emerged as a new layer of epigenetic gene regulation. N6-methyladenosine (m6A) is the most abundant chemical modification of messenger RNA (mRNA), yet the role of m6A modification in PARPi resistance has not previously been explored. Here we show that m6A modification of FZD10 mRNA contributes to PARPi...
42 CitationsSource
#1Nkechiyere G. Nwani (NU: Northwestern University)H-Index: 4
#2Salvatore Condello (IUPUI: Indiana University – Purdue University Indianapolis)H-Index: 18
Last. Daniela Matei (NU: Northwestern University)H-Index: 59
view all 7 authors...
A small of population of slow cycling and chemo-resistant cells referred to as cancer stem cells (CSC) have been implicated in cancer recurrence. There is emerging interest in developing targeted therapeutics to eradicate CSCs. Aldehyde-dehydrogenase (ALDH) activity was shown to be a functional marker of CSCs in ovarian cancer (OC). ALDH activity is increased in cells grown as spheres versus monolayer cultures under differentiating conditions and in OC cells after treatment with platinum. Here, ...
15 CitationsSource
#1Yilong Zou (Broad Institute)H-Index: 18
#2Michael J. Palte (Broad Institute)H-Index: 7
Last. Stuart L. Schreiber (Broad Institute)H-Index: 141
view all 20 authors...
Clear-cell carcinomas (CCCs) are a histological group of highly aggressive malignancies commonly originating in the kidney and ovary. CCCs are distinguished by aberrant lipid and glycogen accumulation and are refractory to a broad range of anti-cancer therapies. Here we identify an intrinsic vulnerability to ferroptosis associated with the unique metabolic state in CCCs. This vulnerability transcends lineage and genetic landscape, and can be exploited by inhibiting glutathione peroxidase 4 (GPX4...
97 CitationsSource
#1Xiaofen Pan (Guangdong Medical College)H-Index: 3
#2Zhi-Xiu Lin (Guangdong Medical College)H-Index: 1
Last. Zhonghua Yu (Guangdong Medical College)H-Index: 7
view all 11 authors...
: The aim of the present study was to examine whether erastin influences radioresistance in non-small cell lung cancer (NSCLC) cells and produce a preliminary investigation into its mechanism of action. The radioresistant subtype of NSCLC cells, A549-R and H460-R, were induced by high-dose hypofractionated irradiation. Erastin was used to treat the radioresistant cells and radiosensitivity was examined by colony formation assays. Cell death was determined after the cells were treated with erasti...
24 CitationsSource
#1Tobias Seibt (LMU: Ludwig Maximilian University of Munich)H-Index: 3
#2Bettina PronethH-Index: 9
Last. Marcus ConradH-Index: 61
view all 3 authors...
Abstract Ferroptosis is a non-apoptotic form of cell death characterized by iron-dependent lipid peroxidation and metabolic constraints. Dependence on NADPH/H+, polyunsaturated fatty acid metabolism, and the mevalonate and glutaminolysis metabolic pathways have been implicated in this novel form of regulated necrotic cell death. Genetic studies performed in cells and mice established the selenoenzyme glutathione peroxidase (GPX4) as the key regulator of this form of cell death. Besides these gen...
100 CitationsSource
#1Yinu Wang (IU: Indiana University)H-Index: 4
#1Yinu Wang (IU: Indiana University)H-Index: 8
Last. Kenneth P. Nephew (IU: Indiana University)H-Index: 70
view all 6 authors...
: In high-grade serous ovarian cancer (OC), chemotherapy eliminates the majority of tumor cells, leaving behind residual tumors enriched in OC stem cells (OCSC). OCSC, defined as aldehyde dehydrogenase-positive (ALDH+), persist and contribute to tumor relapse. Inflammatory cytokine IL-6 is elevated in residual tumors after platinum treatment, and we hypothesized that IL-6 plays a critical role in platinum-induced OCSC enrichment. We demonstrate that IL-6 regulates stemness features of OCSC drive...
36 CitationsSource
#1Xinbing Sui (Hangzhou Normal University)H-Index: 29
#2Ruonan Zhang (Hangzhou Normal University)H-Index: 6
Last. Tian Xie (Hangzhou Normal University)H-Index: 13
view all 11 authors...
Ferroptosis is an iron-dependent, oxidative cell death, and is characterized by iron-dependent accumulation of reactive oxygen species (ROS) within the cell. It has been implicated in various human diseases, including cancer. Recently, ferroptosis as a non-apoptotic form of cell death induced by small molecules is emerging in specific cancer types, however, its relevance in colorectal cancer (CRC) is unexplored and remains unclear. Here, we showed that ferroptosis inducer RSL3 initiated cell dea...
45 CitationsSource
Cited By0