Characterization of ROS Metabolic Equilibrium Reclassifies Pan-Cancer Samples and Guides Pathway Targeting Therapy.

Tianqi Liu,Shuai Shen,Chen Chen,Gefei Guan,Ling Chen,Chen Zhu,Wen Cheng,Peng Cheng,Jianqi Wu,Cunyi Zou,Zihao Yan,Qing Guo,Xing Liu,Anhua Wu

doi:10.3389/fonc.2020.581197

Abstract

Background: Abnormal redox equilibrium is a major contributor to tumor malignancy and treatment resistance. Understanding reactive oxygen species (ROS) metabolism is a key to clarify the tumor redox status. However, we have limited methods to evaluate ROS in tumor tissues and little knowledge on ROS metabolism across human cancers.Methods: The Cancer Genome Atlas multi-omics data across 22 cancer types and the Genomics of Drug Sensitivity in Cancer data were analyzed in this study. Cell viability testing and xenograft model were used to validate the role of ROS modulation in regulating treatment efficacy.Results: ROS indexes reflecting ROS metabolic balance in five dimensions were developed and verified. Based on the ROS indexes, we conducted ROS metabolic landscape across 22 cancer types and found that ROS metabolism played various roles in different cancer types. Tumor samples were classified into eight ROS clusters with distinct clinical and multi-omics features, which was independent of their histological origin. We established a ROS-based drug efficacy evaluation network and experimentally validated the predicted effects, suggesting that modulating ROS metabolism improves treatment sensitivity and expands drug application scopes.Conclusion: Our study proposes a new method in evaluating ROS status and offers comprehensive understanding on ROS metabolic equilibrium in human cancers, which provide practical implications for clinical management.

Highlights

On a global level, cancer is a dominant and burdensome challenge for modern molecular medicine [1]
Proper relatively low reactive oxygen species (ROS) level is essential for maintaining cellular processes since it can work as a second messenger to facilitate the proliferation of cells, whereas excessive ROS accumulation is toxic, forcing cells to endure harmful oxidative stress conditions
We observed that anti-tumor drug efficacy was predicted by our indexes; we demonstrated that treatment efficacy was improved by modulating ROS metabolism

Summary

Introduction

Cancer is a dominant and burdensome challenge for modern molecular medicine [1]. Proper relatively low ROS level is essential for maintaining cellular processes since it can work as a second messenger to facilitate the proliferation of cells, whereas excessive ROS accumulation is toxic, forcing cells to endure harmful oxidative stress conditions. Cancer cells lie in increased ROS levels due to over-activated oxygen metabolism. As a consequence, these cells develop sophisticated anti-oxidant systems to maintain ROS levels at optimal concentrations [6]. The exploration of ROS status across cancer types is urgently required to clarify ROS metabolic equilibrium in tumor biology. Understanding reactive oxygen species (ROS) metabolism is a key to clarify the tumor redox status. We have limited methods to evaluate ROS in tumor tissues and little knowledge on ROS metabolism across human cancers

Methods

Results

Conclusion