PO.MCB01.01 · 分子与细胞生物学
通过单细胞DNA测序解析乳腺癌演进中的端粒长度动态
Resolving telomere length dynamics in breast cancer evolution through single-cell DNA sequencing
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
端粒通过两个检查点——复制性衰老和端粒危机——限制基因组突变的累积，从而作为关键的肿瘤抑制屏障发挥作用。绕过衰老并进入端粒危机的细胞会经历由端-端融合和有丝分裂缺陷驱动的严重染色体不稳定，这通常导致细胞死亡。少数激活端粒维持机制（例如端粒酶）的稀有细胞能够重新延长端粒、逃逸危机并稳定其基因组，同时可能利用短暂的不稳定性来驱动间断性拷贝数演进和肿瘤发生。尽管端粒在复制性死亡和维持基因组稳定性方面具有重要意义，但由于纵向患者样本有限以及端粒测量的技术挑战（通常需要大量输入材料且与多组学分析不兼容），肿瘤演进过程中端粒长度的动态变化仍知之甚少。为克服这些障碍，我们开发了一种从单细胞DNA测序和多组学数据推断端粒长度的方法。我们在细胞系中验证了该方法，并将其应用于以前所未有的分辨率研究ER阳性（N = 7）和ER阴性（N = 14）乳腺肿瘤中的端粒长度动态。我们的分析揭示了亚克隆多样化过程中端粒长度的显著变化，突显端粒动态是乳腺肿瘤演进的关键特征。系统发育重建揭示了肿瘤特异性的端粒长度演进模式，可能具有临床意义。此外，我们发现亚克隆之间的端粒长度变异与适应度差异和端粒维持通路活性差异相关。这项工作引入了一种强大的工具，可直接在患者肿瘤中以单细胞分辨率探究端粒生物学，为端粒动态在癌症演进中的作用提供了新见解，并为未来研究阐明癌症中端粒调控的生物学和临床意义奠定了基础
查看英文原文 English abstract
Telomeres serve as a critical tumor-suppressive barrier by limiting the accumulation of genomic mutations through two checkpoints: replicative senescence and telomere crisis. Cells that bypass senescence and enter telomere crisis experience rampant chromosomal instability driven by end-to-end fusions and mitotic defects, which typically results in cell death. Rare cells that activate a telomere maintenance mechanism (e.g., telomerase) can re-lengthen telomeres, escape crisis, and stabilize their genome while potentially leveraging transient instability to fuel punctuated copy number evolution and tumorigenesis. Despite their importance in replicative mortality and maintaining genomic stability, the dynamics of telomere length during tumor evolution remain poorly understood due to limited longitudinal patient samples and technical challenges in telomere measurement, which often require large input material and lack compatibility with multiomic profiling. To overcome these barriers, we developed a method to infer telomere length from single-cell DNA sequencing and multiomic data. We validated this approach in cell lines and applied it to study the telomere length dynamics in ER-positive (N = 7) and ER-negative (N = 14) breast tumors with unprecedented resolution. Our analysis revealed substantial telomere length changes during subclonal diversification, highlighting telomere dynamics as a key feature of breast tumor evolution. Phylogenetic reconstruction uncovered tumor-specific patterns of telomere length evolution, which may have clinical implications. Furthermore, we found that telomere length variation among subclones was associated with differences in fitness and telomere maintenance pathway activity. This work introduces a powerful tool to interrogate telomere biology directly in patient tumors at single-cell resolution, providing new insights into the role of telomere dynamics in cancer evolution and laying the foundation for future studies to clarify the biological and clinical significance of telomere regulation in cancer
利益披露 Disclosure
N. Baudoin, None..
C. Tang, None.