THER: integrative web tool for tumor hypoxia exploration and research

Tumor hypoxia refers to the gradual decrease in ATP production when oxygen levels drop below a critical threshold, contributing to malignant tumor development. Studies show hypoxia-induced changes play an indispensable role in tumor progression, enabling tumors to become invasive or metastatic. However, hypoxia's effects vary across tumor types, and these mechanistic differences remain unclear.

To address this, we developed THER (https://smuonco.shinyapps.io/THER/), an online tool that allows analysis of hypoxia-associated transcriptomic data without requiring programming skills. THER contains 63 preprocessed datasets from GEO covering 18 cancer types, with five analysis modules: differential expression, expression profiling, correlation, enrichment, and drug sensitivity analysis.

The differential expression module uses limma to compare gene expression between hypoxia and normoxia groups, presenting results via volcano plots, heatmaps and tables. The expression profiling module presents the expression values of the genes in different oxygen states and employs Mann-Whitney U tests to examine single/multiple gene expression differences. The correlation module explores correlation between the expression of different genes, the expression of genes and the relative expression activity of a pathways, or the relative expression activity of different pathways through scatter plots, heatmaps and chord diagrams. The enrichment module identifies hypoxia-related pathways, while the drug sensitivity module analyzes differential drug responses under varying oxygen conditions.

Experimental validation confirmed THER's reliability. Using the drug sensitivity module, we observed hypoxic MCF7 cells showed significantly higher IC50 values for 51 chemotherapeutic drugs, indicating reduced drug sensitivity. Further analysis with lung cancer cell lines revealed hypoxia-induced resistance to common chemotherapeutics. Experimental tests with three lung cancer cell lines and five drugs confirmed these findings, demonstrating hypoxia's broad impact on drug efficacy across tumor types.

"These results highlight THER's robustness for both research and clinical applications," noted the authors. The tool's ability to uncover hypoxia's variable effects across cancers provides important insights for developing targeted therapies. By enabling systematic analysis of hypoxia's role in tumor progression and drug resistance, THER offers valuable guidance for tumor diagnosis and treatment strategy development.