Yuan Zihao, Fan Xuejun, Zhu Jay-Jiguang, Fu Tong-Ming, Wu Jiaqian, Xu Hua, Zhang Ningyan, An Zhiqiang, Zheng W Jim
School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, TX, USA.
Texas Therapeutics Institute, Institute of Molecular Medicine, McGovern Medical SchoolUniversity of Texas Health Science Center at Houston, Houston, TX, USA.
Nat Commun. 2021 Apr 1;12(1):2031. doi: 10.1038/s41467-021-22200-5.
Patient-derived xenografts are crucial for drug development but their use is challenged by issues such as murine viral infection. We evaluate the scope of viral infection and its impact on patient-derived xenografts by taking an unbiased data-driven approach to analyze unmapped RNA-Seq reads from 184 experiments. We find and experimentally validate the extensive presence of murine viral sequence reads covering entire viral genomes in patient-derived xenografts. The existence of viral sequences inside tumor cells is further confirmed by single cell sequencing data. Extensive chimeric reads containing both viral and human sequences are also observed. Furthermore, we find significantly changed expression levels of many cancer-, immune-, and drug metabolism-related genes in samples with high virus load. Our analyses indicate a need to carefully evaluate the impact of viral infection on patient-derived xenografts for drug development. They also point to a need for attention to quality control of patient-derived xenograft experiments.
患者来源的异种移植对于药物开发至关重要，但其应用受到诸如鼠类病毒感染等问题的挑战。我们采用无偏倚的数据驱动方法，分析来自184个实验的未映射RNA测序读数，以评估病毒感染的范围及其对患者来源的异种移植的影响。我们发现并通过实验验证了患者来源的异种移植中广泛存在覆盖整个病毒基因组的鼠类病毒序列读数。肿瘤细胞内病毒序列的存在通过单细胞测序数据得到进一步证实。还观察到大量同时包含病毒和人类序列的嵌合读数。此外，我们发现在病毒载量高的样本中，许多与癌症、免疫和药物代谢相关的基因表达水平发生了显著变化。我们的分析表明，需要仔细评估病毒感染对用于药物开发的患者来源的异种移植的影响。它们还指出需要关注患者来源的异种移植实验的质量控制。
