Butler George, Amend Sarah R, Venditti Chris, Pienta Kenneth J
Cancer Ecology Center, The Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
School of Biological Sciences, University of Reading, Reading RG6 6AS, UK.
Proc Biol Sci. 2025 Jan;292(2039):20242850. doi: 10.1098/rspb.2024.2850. Epub 2025 Jan 22.
The evolution of metastasis, the spread of cancer to distal sites within the body, represents a lethal stage of cancer progression. Yet, the evolutionary dynamics that shape the emergence of metastatic disease remain unresolved. Here, using single-cell lineage tracing data in combination with phylogenetic statistical methods, we show that the evolutionary trajectory of metastatic disease is littered with bursts of rapid molecular change as new cellular subpopulations appear, a pattern known as punctuational evolution. Next, by measuring punctuational evolution across the metastatic cascade, we show that punctuational effects are concentrated within the formation of secondary tumours at distal metastatic sites, suggesting that qualitatively different modes of evolution may drive primary and metastatic tumour progression. Taken as a whole, our findings provide empirical evidence for distinct patterns of molecular evolution at early and late stages of metastatic disease and our approach provides a framework to study the evolution of metastasis at a more nuanced level than has been previously possible.
转移（即癌症扩散至身体远端部位）的演变是癌症进展的致命阶段。然而，塑造转移性疾病出现的进化动力学仍未得到解决。在这里，我们结合系统发育统计方法使用单细胞谱系追踪数据，表明转移性疾病的进化轨迹充斥着随着新细胞亚群出现而产生的快速分子变化爆发，这种模式被称为间断性进化。接下来，通过测量整个转移级联过程中的间断性进化，我们表明间断性效应集中在远端转移部位继发性肿瘤的形成过程中，这表明性质不同的进化模式可能驱动原发性和转移性肿瘤的进展。总体而言，我们的研究结果为转移性疾病早期和晚期分子进化的不同模式提供了实证依据，并且我们的方法提供了一个框架，能够以比以往更细致入微的水平研究转移的进化。
