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新研究从单细胞癌症基因组的时间序列模型中推断出克隆适应性
2021-06-27 16:06

美国纪念斯隆-凯特琳癌症中心Sohrab P. Shah、Samuel Aparicio等研究人员合作从单细胞癌症基因组的时间序列模型中推断出克隆适应性。这一研究成果于2021年6月23日在线发表在国际学术期刊《自然》上。

研究人员从乳腺上皮和原发性三阴性乳腺癌(TNBC)患者来源异种移植物(PDX)的多年时间序列单细胞全基因组测序中生成了42,000个基因组,从而揭示了拷贝数改变(CNA)定义的克隆适应性动态的本质,这是由TP53突变和顺铂化疗诱导的。使用新的Wright-Fisher群体遗传学模型来推断克隆适应性,研究人员发现TP53突变改变了适应性景观,可重复地将适应性分布在与不同CNA相关的大量克隆上。

此外,在具有突变TP53的TNBC PDX模型中,从基于CNA基因型推断出的适应度系数准确地预测了实验得到的克隆竞争动态。在三个长期连续传代的TNBC PDX中进行药物治疗导致在未经治疗的环境中从低适应性系统发育谱系中出现顺铂抗性克隆。相反,来自未经治疗对照的高适应度克隆被根除,这表明适应度景观发生逆转。最后,在药物释放后,选择压力动态发生逆转,这表明治疗抵抗的适应成本。

总之,这些研究结果定义了与多克隆肿瘤中的CNA以及治疗抵抗相关的克隆适应性。

据了解,由于缺乏多克隆种群的时间序列单细胞采样和时间统计模型,在定义癌症基因组适应性景观方面的进展,尤其是那些由拷贝数改变CNA定义的情况,受到了阻碍。

附:英文原文

Title: Clonal fitness inferred from time-series modelling of single-cell cancer genomes

Author: Sohrab Salehi, Farhia Kabeer, Nicholas Ceglia, Mirela Andronescu, Marc J. Williams, Kieran R. Campbell, Tehmina Masud, Beixi Wang, Justina Biele, Jazmine Brimhall, David Gee, Hakwoo Lee, Jerome Ting, Allen W. Zhang, Hoa Tran, Ciara OFlanagan, Fatemeh Dorri, Nicole Rusk, Teresa Ruiz de Algara, So Ra Lee, Brian Yu Chieh Cheng, Peter Eirew, Takako Kono, Jenifer Pham, Diljot Grewal, Daniel Lai, Richard Moore, Andrew J. Mungall, Marco A. Marra, Andrew McPherson, Alexandre Bouchard-Ct, Samuel Aparicio, Sohrab P. Shah

Issue&Volume: 2021-06-23

Abstract: Progress in defining genomic fitness landscapes in cancer, especially those defined by copy number alterations (CNAs), has been impeded by lack of time-series single-cell sampling of polyclonal populations and temporal statistical models1,2,3,4,5,6,7. Here we generated 42,000 genomes from multi-year time-series single-cell whole-genome sequencing of breast epithelium and primary triple-negative breast cancer (TNBC) patient-derived xenografts (PDXs), revealing the nature of CNA-defined clonal fitness dynamics induced by TP53 mutation and cisplatin chemotherapy. Using a new Wright–Fisher population genetics model8,9 to infer clonal fitness, we found that TP53 mutation alters the fitness landscape, reproducibly distributing fitness over a larger number of clones associated with distinct CNAs. Furthermore, in TNBC PDX models with mutated TP53, inferred fitness coefficients from CNA-based genotypes accurately forecast experimentally enforced clonal competition dynamics. Drug treatment in three long-term serially passaged TNBC PDXs resulted in cisplatin-resistant clones emerging from low-fitness phylogenetic lineages in the untreated setting. Conversely, high-fitness clones from treatment-naive controls were eradicated, signalling an inversion of the fitness landscape. Finally, upon release of drug, selection pressure dynamics were reversed, indicating a fitness cost of treatment resistance. Together, our findings define clonal fitness linked to both CNA and therapeutic resistance in polyclonal tumours.

DOI: 10.1038/s41586-021-03648-3

Source: https://www.nature.com/articles/s41586-021-03648-3

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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