The Effects of Heat Stress on the Transcriptome of Human Cancer Cells: A Meta-Analysis

SIMPLE SUMMARY: When exposed to heat, and other forms of stress, mammalian cells activate a rich and diverse network of processes, pathways and genes which, together, protect them from damage. Even though this process, termed the heat stress response, has been studied extensively for many decades, and is particularly relevant in the context of cancer (treatment), its systemic understanding is still beyond our reach. Here, we explored one aspect of the heat stress response in cancer cells—changes in gene expression—by subjecting 18 datasets to extensive meta-analysis. We found a surprisingly high level of inter-study variability, driven at least in part by the different experimental conditions applied in each study, and an apparent absence of a ‘universal’ gene expression signature. Our results suggest that gene expression changes after heat stress may be largely determined by the experimental context and call for a more extensive, controlled study that examines the effects of key experimental parameters. ABSTRACT: Hyperthermia is clinically applied cancer treatment in conjunction with radio- and/or chemotherapy, in which the tumor volume is exposed to supraphysiological temperatures. Since cells can effectively counteract the effects of hyperthermia by protective measures that are commonly known as the heat stress response, the identification of cellular processes that are essential for surviving hyperthermia could lead to novel treatment strategies that improve its therapeutic effects. Here, we apply a meta-analytic approach to 18 datasets that capture hyperthermia-induced transcriptome alterations in nine different human cancer cell lines. We find, in line with previous reports, that hyperthermia affects multiple processes, including protein folding, cell cycle, mitosis, and cell death, and additionally uncover expression changes of genes involved in KRAS signaling, inflammatory responses, TNF-a signaling and epithelial-to-mesenchymal transition (EMT). Interestingly, however, we also find a considerable inter-study variability, and an apparent absence of a ‘universal’ heat stress response signature, which is likely caused by the differences in experimental conditions. Our results suggest that gene expression alterations after heat stress are driven, to a large extent, by the experimental context, and call for a more extensive, controlled study that examines the effects of key experimental parameters on global gene expression patterns.