Aberrant R-loop–mediated immune evasion, cellular communication, and metabolic reprogramming affect cancer progression: a single-cell analysis

作者：Shichao Zhang, Yang Liu, Yichi Sun, Qin Liu, Yan Gu, Ya Huang, Zhu Zeng, Fuzhou Tang, Yan Ouyang · 发表于：Molecular Cancer · 年份：2024 · DOI：10.1186/s12943-023-01924-6 · 被引用次数：59 · 研究领域：Tryptophan and brain disorders、DNA Repair Mechanisms、Cancer, Hypoxia, and Metabolism

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 mo...