Non-genetic heterogeneity observed in clonal cell populations is an immediate cause of drug resistance that remains challenging to profile because of its transient nature. Here, we coupled three single-cell technologies to link the predicted drug response of a cell to its own genome-wide transcriptomic profile. As a proof of principle, we analyzed the response to tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) in HeLa cells to demonstrate that cell dynamics can discriminate the transient transcriptional states at the origin of cell decisions such as sensitivity and resistance. Our same-cell approach, named fate-seq, can reveal the molecular factors regulating the efficacy of a drug in clonal cells, providing therapeutic targets of non-genetic drug resistance otherwise confounded in gene expression noise. A record of this paper’s transparent peer review process is included in the Supplemental Information.

在克隆细胞群中观察到的非遗传异质性是耐药性的直接原因，由于其短暂的性质，耐药性仍然具有挑战性。在这里，我们结合了三种单细胞技术，将细胞的预测药物反应与其自身的全基因组转录组谱联系起来。作为原理证明，我们分析了 HeLa 细胞对肿瘤坏死因子相关凋亡诱导配体 (TRAIL) 的反应，以证明细胞动力学可以区分细胞决定起源时的瞬时转录状态，例如敏感性和抗性. 我们的同细胞方法，命名为命运序列，可以揭示在克隆细胞中调节药物功效的分子因素，提供非遗传耐药性的治疗靶点，否则会被基因表达噪声混淆。