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科学家实现可导致治疗耐药的单细胞变异性调节因子的遗传筛选
2021-01-06 17:29

美国宾夕法尼亚大学Arjun Raj、Junwei Shi等研究人员合作实现可导致治疗耐药的单细胞变异性调节因子的遗传筛选。这一研究成果于2021年1月4日在线发表在国际学术期刊《自然—遗传学》上。

研究人员使用了CRISPR–Cas9基因筛查来鉴定可通过改变细胞可塑性来影响细胞命运决定的基因。研究人员发现许多因素可以独立地影响细胞启动和命运的决定。研究人员发现了一种新的可塑性模式,该模式增加了对BRAF抑制的抗性,并将细胞推向更加分化的状态。在添加BRAF抑制剂之前,通过抑制DOT1L来操纵细胞可塑性比同时给药产生更大的治疗抵抗力。这些结果表明,调节细胞可塑性可以改变细胞命运的决定,并可能被证明可用于治疗其他癌症的耐药性。

据介绍,细胞可塑性描述了细胞从一组表型转变为另一组表型的能力。在黑色素瘤中,肿瘤细胞分子状态的瞬时波动标志着稀有细胞的形成,这些稀有细胞可以抵抗BRAF抑制并重新编程为稳定的耐药性。然而,控制细胞启动的生物学过程仍是未知的。

附:英文原文

Title: Genetic screening for single-cell variability modulators driving therapy resistance

Author: Eduardo A. Torre, Eri Arai, Sareh Bayatpour, Connie L. Jiang, Lauren E. Beck, Benjamin L. Emert, Sydney M. Shaffer, Ian A. Mellis, Mitchell E. Fane, Gretchen M. Alicea, Krista A. Budinich, Ashani T. Weeraratna, Junwei Shi, Arjun Raj

Issue&Volume: 2021-01-04

Abstract: Cellular plasticity describes the ability of cells to transition from one set of phenotypes to another. In melanoma, transient fluctuations in the molecular state of tumor cells mark the formation of rare cells primed to survive BRAF inhibition and reprogram into a stably drug-resistant fate. However, the biological processes governing cellular priming remain unknown. We used CRISPR–Cas9 genetic screens to identify genes that affect cell fate decisions by altering cellular plasticity. We found that many factors can independently affect cellular priming and fate decisions. We discovered a new plasticity-based mode of increasing resistance to BRAF inhibition that pushes cells towards a more differentiated state. Manipulating cellular plasticity through inhibition of DOT1L before the addition of the BRAF inhibitor resulted in more therapy resistance than concurrent administration. Our results indicate that modulating cellular plasticity can alter cell fate decisions and may prove useful for treating drug resistance in other cancers.

DOI: 10.1038/s41588-020-00749-z

Source: https://www.nature.com/articles/s41588-020-00749-z

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:41.307
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex


本期文章:《自然—遗传学》:Online/在线发表

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