Unraveling bidirectional evolution of unstable mitochondrial DNA mutations in hepatocellular carcinoma at single-cell resolution

异质性 线粒体DNA 体细胞 生物 癌变 癌症的体细胞进化 单细胞分析 突变 细胞 遗传学 分子生物学 癌症研究 癌症 基因
作者
Kai-Xiang Zhou,Z Q Wang,Wenjie Guo,Fanfan Xie,Qing Yuan,Shanshan Guo,Huanqin Zhang,Yang Liu,Xiwen Gu,Wenjie Song,Xu Guo,Jinliang Xing
出处
期刊:Hepatology [Lippincott Williams & Wilkins]
标识
DOI:10.1097/hep.0000000000001113
摘要

Background and Aims: Somatic mutations in mitochondrial DNA (mtDNA) are abundant in HCC and directly affect metabolic homeostasis and tumor progression. The mixed population of mutant and wild-type mtDNA alleles within a cell, termed heteroplasmy, can vary from cell-to-cell and orchestrate tumorigenesis. However, the systematic evolutionary dynamics of somatic mtDNA mutations in HCC tissues remain to be delineated at single-cell resolution. Approach and Results: We established the single-cell capture-based mtDNA sequencing approach for accurately detecting somatic mtDNA mutations at single-cell resolution. Based on single-cell capture-based mtDNA sequencing, the single-cell somatic mtDNA mutational landscape, intratumor heterogeneity (ITH), and spatiotemporal clonal evolution were systematically investigated in 1641 single cells from 11 patients with HCC and 528 single cells from 2 patient-derived xenografts mouse models. Our data revealed the presence of 2 distinct categories of mtDNA mutation at single-cell resolution, including stable mutations exhibiting similar heteroplasmy levels and unstable mutations exhibiting remarkable cell-to-cell variability of heteroplasmy levels. Furthermore, the proportion of unstable mtDNA mutations was positively associated with the ITH of patients with HCC, with high ITH reflecting the proliferative and aggressive clinicopathological features of HCC cells. In addition, reconstruction of the evolutionary history classified HCC evolution patterns as linear or branched. Notably, spatiotemporal lineage tracing in patient-derived xenograft mouse models and multifocal lesions revealed bidirectional evolution of unstable mtDNA mutations during HCC progression. Conclusions: Our study unravels the landscape of single-cell somatic mtDNA mutations in HCC tissues and reveals the bidirectional evolution of unstable mtDNA mutations, with potential implications for HCC stratification and therapeutic intervention.
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