Abou Khouzam Raefa, Sharda Mohak, Rao Shyama Prasad, Kyerewah-Kersi Stephanie Maame, Zeinelabdin Nagwa Ahmed, Mahmood Ayda Shah, Nawafleh Husam, Khan Munazza Samar, Venkatesh Goutham Hassan, Chouaib Salem
Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates.
National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, Karnataka, India.
Front Cell Dev Biol. 2023 Mar 9;11:1095419. doi: 10.3389/fcell.2023.1095419. eCollection 2023.
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 ( = 0.03) and copy number losses ( = 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.
缺氧困扰实体瘤的微环境，助长恶性肿瘤。我们研究了长期缺氧暴露对转录重塑、肿瘤突变负担（TMB）以及基于其对缺氧的固有敏感性或抗性分组的癌细胞基因组不稳定性的影响。缺氧评分被用作区分对缺氧最敏感（高缺氧（HH））和最具抗性（低缺氧（HL））癌细胞的指标。通过应用全外显子组测序和微阵列分析，我们表明HH组确实对缺氧更敏感，具有显著更高的TMB（ = 0.03）和拷贝数丢失（ = 0.03），以及更高转录反应的趋势。总体而言，细胞通过降低参与代谢、增殖和蛋白质成熟的基因表达以及增加可变剪接来适应。它们积累突变，尤其是移码插入，并存在增加的拷贝数改变，表明基因组不稳定性增加。显示最高TMB的细胞同时经历了DNA复制和修复以及染色体维持途径的显著下调。提出了对慢性缺氧的十六基因共同反应，包括调节血管生成和增殖的基因。我们的研究结果表明，慢性缺氧通过代谢重编程、调节增殖和增加基因组不稳定性来使肿瘤细胞存活。它们还突出了关键的适应性途径，这些途径可能成为潜在靶点，以防止存在于慢性缺氧肿瘤区域的癌细胞茁壮成长。
