Multi-Omics Analysis of Cancer Cell Lines with High/Low Ferroptosis Scores and Development of a Ferroptosis-Related Model for Multiple Cancer Types

Abstract

Background: Ferroptosis is a newly identified regulated cell death characterized by iron-dependent lipid peroxidation and subsequent membrane oxidative damage, which has been implicated in multiple types of cancers. The multi-omics differences between cancer cell lines with high/low ferroptosis scores remain to be elucidated.Methods and Materials: We used RNA-seq gene expression, gene mutation, miRNA expression, metabolites, copy number variation, and drug sensitivity data of cancer cell lines from DEPMAP to detect multi-omics differences associated with ferroptosis. Based on the gene expression data of cancer cell lines, we performed LASSO-Logistic regression analysis to build a ferroptosis-related model. Lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), esophageal cancer (ESCA), bladder cancer (BLCA), cervical cancer (CESC), and head and neck cancer (HNSC) patients from the TCGA database were used as validation cohorts to test the efficacy of this model.Results: After stratifying the cancer cell lines into high score (HS) and low score (LS) groups according to the median of ferroptosis scores generated by gene set variation analysis, we found that IC50 of 66 agents such as oxaliplatin (p < 0.001) were significantly different, among which 65 were higher in the HS group. 851 genes such as KEAP1 and NRAS were differentially muted between the two groups. Differentially expressed genes, miRNAs and metabolites were also detected—multiple items such as IL17F (logFC = 6.58, p < 0.001) differed between the two groups. Unlike the TCGA data generated by bulk RNA-seq, the gene expression data in DEPMAP are from pure cancer cells, so it could better reflect the traits of tumors in cancer patients. Thus, we built a 15-signature model (AUC = 0.878) based on the gene expression data of cancer cell lines. The validation cohorts demonstrated a higher mutational rate of NFE2L2 and higher expression levels of 12 ferroptosis-related genes in HS groups.Conclusion: This article systemically analyzed multi-omics differences between cancer cell lines with high/low ferroptosis scores and a ferroptosis-related model was developed for multiple cancer types. Our findings could improve our understanding of the role of ferroptosis in cancer and provide new insight into treatment for malignant tumors.

Ferroptosis Induction Improves the Sensitivity of Docetaxel in Prostate Cancer

“…Recent studies have confirmed that a variety of FDA-approved drugs, such as flubendazole [20], brequinar [6], and sulfasalazine [27], can play an antitumor role by inducing ferroptosis, indicating the feasibility of such drugs in combination with chemotherapy. Previous studies have shown that FINs can improve the sensitivity of a variety of chemotherapeutic drugs including docetaxel [28], cisplatin [29], and oxaliplatin [30]. A recent study has confirmed that FINs were found to significantly improve the efficacy of antiandrogenic drugs for PCa without increasing side effects [15].…”

Ferroptosis-Associated Molecular Features to Aid Patient Clinical Prognosis and Therapy Across Human Cancers

“…Previous studies have analyzed ferroptosis-correlated signatures or genes in single-types of cancer, but we noted that a systematic landscape of associations among tumor ferroptosis, clinical outcomes, tumor microenvironment, and therapies in human cancers is lacking. Besides, recent studies have also analyzed ferroptosis-correlated molecular signatures and constructed scores for these cancer types (5)(6)(7). However, most of these studies analyzed ferroptosis signatures without distinguishing between drive and suppress regulators.…”

“…Moreover, since ferroptosis has been reported to be related to cancer immunity, activation of ferroptosis may serve as a new strategy for developing of anti-cancer agents with immunotherapeutic potential (4). Several recent studies have identified ferroptosis-correlated molecular signatures in multiple cancer types (5)(6)(7). Nevertheless, these studies used ferroptosis regulators without distinguishing between drive and suppress regulators.…”

Ferroptosis: The Entanglement between Traditional Drugs and Nanodrugs in Tumor Therapy

“…Since various types of cancer have different sensitivities to ferroptosis, the choice of small molecule drugs needs to be further investigated. [ 57 ]…”