Chronic hypoxia is associated with transcriptomic reprogramming and increased genomic instability in cancer cells

Hypoxia afflicts the microenvironment of solid tumors fueling malignancy. We investigated the impact of long hypoxia exposure on transcriptional remodeling, tumor mutational burden (TMB), and genomic instability of cancer cells that were grouped based on their inherent sensitivity or resistance to hypoxia. A hypoxia score was used as a metric to distinguish between the most hypoxia-sensitive (hypoxia high (HH)), and most resistant (hypoxia low (HL)) cancer cells. By applying whole exome sequencing and microarray analysis, we showed that the HH group was indeed more sensitive to hypoxia, having significantly higher TMB (p = 0.03) and copy number losses (p = 0.03), as well as a trend of higher transcriptional response. Globally cells adapted by decreasing expression of genes involved in metabolism, proliferation, and protein maturation, and increasing alternative splicing. They accumulated mutations, especially frameshift insertions, and harbored increased copy number alterations, indicating increased genomic instability. Cells showing highest TMB simultaneously experienced a significant downregulation of DNA replication and repair and chromosomal maintenance pathways. A sixteen-gene common response to chronic hypoxia was put forth, including genes regulating angiogenesis and proliferation. Our findings show that chronic hypoxia enables survival of tumor cells by metabolic reprogramming, modulating proliferation, and increasing genomic instability. They additionally highlight key adaptive pathways that can potentially be targeted to prevent cancer cells residing in chronically hypoxic tumor areas from thriving.

Automated summary

Hypoxia has a significant impact on the microenvironment of solid tumors, promoting malignancy. In this study, we investigated the effects of long-term hypoxia exposure on transcriptional remodeling, tumor mutational burden (TMB), and genomic instability in cancer cells categorized based on their sensitivity or resistance to hypoxia. Our findings demonstrate that chronic hypoxia leads to metabolic reprogramming, modulation of proliferation, and increased genomic instability in tumor cells. These adaptive responses can be targeted to inhibit the growth and survival of cancer cells in chronically hypoxic tumor areas.