Tumor evolution from a single cell into a malignant, heterogeneous tissue remains poorly understood. Here, we profile single-cell transcriptomes of genetically engineered mouse lung tumors at seven stages, from pre-neoplastic hyperplasia to adenocarcinoma. The diversity of transcriptional states increases over time and is reproducible across tumors and mice. Cancer cells progressively adopt alternate lineage identities, computationally predicted to be mediated through a common transitional, high-plasticity cell state (HPCS). Accordingly, HPCS cells prospectively isolated from mouse tumors and human patient-derived xenografts display high capacity for differentiation and proliferation. The HPCS program is associated with poor survival across human cancers and demonstrates chemoresistance in mice. Our study reveals a central principle underpinning intra-tumoral heterogeneity and motivates therapeutic targeting of the HPCS.

肿瘤从单细胞到恶性异质组织的演化仍然知之甚少。在这里，我们分析了基因工程小鼠肺部肿瘤从肿瘤前期增生到腺癌七个阶段的单细胞转录组。转录状态的多样性随着时间的推移而增加，并且在肿瘤和小鼠中是可重复的。癌细胞逐渐采用替代的谱系身份，计算预测这是通过共同的过渡、高可塑性细胞状态（HPCS）介导的。因此，从小鼠肿瘤和人类患者来源的异种移植物中前瞻性分离的 HPCS 细胞显示出高分化和增殖能力。HPCS 计划与人类癌症的低生存率有关，并在小鼠中表现出化疗耐药性。我们的研究揭示了支撑肿瘤内异质性的核心原理，并激发了 HPCS 的治疗靶向。