美国宾夕法尼亚大学Arjun Raj研究组发现，稀有细胞状态中的变异性为耐药提供多种途径。这一研究成果于2021年2月22日在线发表在国际学术期刊《自然—生物技术》上。

研究人员开发了Rewind，该方法将遗传条形码与RNA荧光原位杂交相结合，可以直接捕获引起感兴趣细胞行为的稀有细胞。将Rewind应用于BRAFV600E黑色素瘤，研究人员可以将耐药细胞的命运追溯到其原始药物前体中的单细胞基因表达差异（初始频率约为1：1,000-1：10,000个细胞）和MAP激酶信号转导后的相对持久性药物治疗。

在这种稀有的亚群中，研究人员发现了一个丰富的亚结构，其中几个不同亚群之间的分子差异预测了表型行为的未来差异，例如药物治疗后不同抗性克隆的增殖能力。这些结果揭示了未知的稀有细胞变异性，该变异性是药物暴露后一系列潜在表型结果的基础。 

据悉，单个细胞之间的分子差异会导致细胞命运的显著差异，例如药物治疗后癌细胞的死亡与存活。由于这些起源差异仍在很大程度上未知，因此难以准确确定哪些可变分子特征会导致什么样的细胞命运。

附：英文原文 

Title: Variability within rare cell states enables multiple paths toward drug resistance

Author: Benjamin L. Emert, Christopher J. Cote, Eduardo A. Torre, Ian P. Dardani, Connie L. Jiang, Naveen Jain, Sydney M. Shaffer, Arjun Raj

Issue&Volume: 2021-02-22

Abstract: Molecular differences between individual cells can lead to dramatic differences in cell fate, such as death versus survival of cancer cells upon drug treatment. These originating differences remain largely hidden due to difficulties in determining precisely what variable molecular features lead to which cellular fates. Thus, we developed Rewind, a methodology that combines genetic barcoding with RNA fluorescence in situ hybridization to directly capture rare cells that give rise to cellular behaviors of interest. Applying Rewind to BRAFV600E melanoma, we trace drug-resistant cell fates back to single-cell gene expression differences in their drug-naive precursors (initial frequency of ~1:1,000–1:10,000 cells) and relative persistence of MAP kinase signaling soon after drug treatment. Within this rare subpopulation, we uncover a rich substructure in which molecular differences among several distinct subpopulations predict future differences in phenotypic behavior, such as proliferative capacity of distinct resistant clones after drug treatment. Our results reveal hidden, rare-cell variability that underlies a range of latent phenotypic outcomes upon drug exposure.

DOI: 10.1038/s41587-021-00837-3

Source: https://www.nature.com/articles/s41587-021-00837-3