Cancer cells exhibit dramatic differences in gene expression at the single-cell level, which can predict whether they become resistant to treatment. Treatment perpetuates this heterogeneity, resulting in a diversity of cell states among resistant clones. However, it remains unclear whether these differences lead to distinct responses when another treatment is applied or the same treatment is continued. In this study, we combined single-cell RNA sequencing with barcoding to track resistant clones through prolonged and sequential treatments. We found that cells within the same clone have similar gene expression states after multiple rounds of treatment. Moreover, we demonstrated that individual clones have distinct and differing fates, including growth, survival, or death, when subjected to a second treatment or when the first treatment is continued. By identifying gene expression states that predict clone survival, this work provides a foundation for selecting optimal therapies that target the most aggressive resistant clones within a tumor. A record of this paper’s transparent peer review process is included in the supplemental information.

中文翻译：

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克隆差异是对序贯和长期治疗的不同反应的基础

癌细胞在单细胞水平上表现出巨大的基因表达差异，这可以预测它们是否会对治疗产生耐药性。治疗使这种异质性永久存在，导致耐药克隆中细胞状态的多样性。然而，目前尚不清楚当应用另一种治疗或继续相同的治疗时，这些差异是否会导致不同的反应。在这项研究中，我们将单细胞 RNA 测序与条形码相结合，通过长期和连续的治疗来追踪耐药克隆。我们发现同一克隆内的细胞经过多轮处理后具有相似的基因表达状态。此外，我们证明，当接受第二次治疗或继续第一次治疗时，各个克隆具有不同的命运，包括生长、存活或死亡。通过识别预测克隆存活的基因表达状态，这项工作为选择针对肿瘤内最具侵袭性的耐药克隆的最佳疗法奠定了基础。补充信息中包含了本文透明同行评审过程的记录。