Aberrant R-loop-mediated immune evasion, cellular communication, and metabolic reprogramming affect cancer progression: a single-cell analysis.
Aberrant R-loop-mediated immune evasion, cellular communication, and metabolic reprogramming affect cancer progression: a single-cell analysis.
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DOI：
10.1186/s12943-023-01924-6
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发表时间：
2024-01-10
期刊：
影响因子：
37.3
通讯作者：
Ouyang, Yan
中科院分区：
文献类型：
--
作者：
Zhang, Shichao;Liu, Yang;Sun, Yichi;Liu, Qin;Gu, Yan;Huang, Ya;Zeng, Zhu;Tang, Fuzhou;Ouyang, Yan
关键词：
R环稳态失调与包括癌症在内的多种人类疾病密切相关。然而，异常R环在肿瘤进展中的因果关系仍不清楚。在这项研究中，使用来自肺腺癌（LUAD）的单细胞RNA测序数据集，我们构建了一个R-loop评分模型，以根据所识别的与EGFR突变、组织来源和TNM分期相关的R-loop调节因子来表征R-loop状态。然后，我们评估了R-loop评分与肿瘤微环境（TME）和治疗反应的关系。此外，FANCI介导的R-环在LUAD中的潜在作用进行了探索，使用一系列的体外实验。结果表明，低R-loop评分的恶性细胞显示糖酵解和上皮-间质转化途径激活和免疫逃逸促进，从而阻碍抗肿瘤治疗效果。细胞通讯分析表明，低的R-环评分有助于T细胞耗竭。我们随后通过使用33种肿瘤类型的批量转录组数据集验证了R环评分的预后价值。R-loop评分模型在32个独立队列中很好地预测了患者对靶向治疗、化疗或免疫治疗的治疗反应。值得注意的是，由FANCI缺陷介导的R环分布的变化阻断了Ras信号通路的活性，抑制了肿瘤细胞的增殖和传播。总之，本研究揭示了R-loop评分模式下代谢重编程和T细胞耗竭的潜在分子机制，以及由R-loop调节因子介导的R-loop变化导致肿瘤进展。因此，将基于R环或R环调节剂的抗癌方法纳入精准医学的治疗方案可能是有益的。在线版本包含补充材料，可通过10.1186/s12943-023-01924-6获得。
Dysregulation of R-loop homeostasis is closely related to various human diseases, including cancer. However, the causality of aberrant R-loops in tumor progression remains unclear. In this study, using single-cell RNA-sequencing datasets from lung adenocarcinoma (LUAD), we constructed an R-loop scoring model to characterize the R-loop state according to the identified R-loop regulators related to EGFR mutations, tissue origins, and TNM stage. We then evaluated the relationships of the R-loop score with the tumor microenvironment (TME) and treatment response. Furthermore, the potential roles of FANCI-mediated R-loops in LUAD were explored using a series of in vitro experiments. Results showed that malignant cells with low R-loop scores displayed glycolysis and epithelial–mesenchymal transition pathway activation and immune escape promotion, thereby hampering the antitumor therapeutic effects. Cell communication analysis suggested that low R-loop scores contributed to T cell exhaustion. We subsequently validated the prognostic value of R-loop scores by using bulk transcriptome datasets across 33 tumor types. The R-loop scoring model well predicted patients’ therapeutic response to targeted therapy, chemotherapy, or immunotherapy in 32 independent cohorts. Remarkably, changes in R-loop distribution mediated by FANCI deficiency blocked the activity of Ras signaling pathway, suppressing tumor-cell proliferation and dissemination. In conclusion, this study reveals the underlying molecular mechanism of metabolic reprogramming and T cell exhaustion under R-loop score patterns, and the changes in R-loops mediated by R-loop regulators resulting in tumor progression. Therefore, incorporating anticancer methods based on R-loop or R-loop regulators into the treatment schemes of precision medicine may be beneficial. The online version contains supplementary material available at 10.1186/s12943-023-01924-6.
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