Tumor evolution is driven by the progressive acquisition of genetic and epigenetic alterations that enable uncontrolled growth and expansion to neighboring and distal tissues. The study of phylogenetic relationships between cancer cells provides key insights into these processes. Here, we introduced an evolving lineage-tracing system with a single-cell RNA-seq readout into a mouse model of Kras;Trp53(KP)-driven lung adenocarcinoma and tracked tumor evolution from single-transformed cells to metastatic tumors at unprecedented resolution. We found that the loss of the initial, stable alveolar-type2-like state was accompanied by a transient increase in plasticity. This was followed by the adoption of distinct transcriptional programs that enable rapid expansion and, ultimately, clonal sweep of stable subclones capable of metastasizing. Finally, tumors develop through stereotypical evolutionary trajectories, and perturbing additional tumor suppressors accelerates progression by creating novel trajectories. Our study elucidates the hierarchical nature of tumor evolution and, more broadly, enables in-depth studies of tumor progression.

肿瘤进化是由遗传和表观遗传改变的逐渐获得所驱动的，这些改变使得肿瘤能够不受控制地生长和扩展到邻近和远端组织。对癌细胞之间系统发育关系的研究为这些过程提供了重要的见解。在这里，我们将一种不断发展的谱系追踪系统与单细胞 RNA-seq 读数引入Kras;Trp53小鼠模型中（KP）驱动的肺腺癌，并以前所未有的分辨率追踪从单一转化细胞到转移性肿瘤的肿瘤演变。我们发现，初始稳定的类肺泡状态的丧失伴随着可塑性的短暂增加。随后采用了独特的转录程序，这些程序能够实现快速扩增，并最终对能够转移的稳定亚克隆进行克隆扫描。最后，肿瘤按照刻板的进化轨迹发展，扰乱额外的肿瘤抑制因子可以通过创造新的轨迹来加速进展。我们的研究阐明了肿瘤进化的层次性质，更广泛地说，使得能够深入研究肿瘤进展。