单细胞基因组学分析揭示了获得性 BRAF 抑制剂耐药性体内模型中复杂的基因相互作用。

IF 3.4 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
NAR cancer Pub Date : 2024-01-11 eCollection Date: 2024-03-01 DOI:10.1093/narcan/zcad061
Jacob L Schillo, Charlotte R Feddersen, Rebekah M Peplinski, Lexy S Powell, Afshin Varzavand, Christopher S Stipp, Jesse D Riordan, Adam J Dupuy
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引用次数: 0

摘要

治疗耐药性的演变是靶向肿瘤药物取得成功的主要障碍。虽然瘤间和瘤内异质性限制了我们检测治疗前存在或治疗过程中出现的耐药亚群的能力,但我们以单细胞分辨率分析肿瘤的能力也很有限。在这里,我们利用基于细胞的转座子诱变方法来确定皮肤黑色素瘤模型中 BRAF 抑制剂的耐药机制。这一筛选确定了 NEDD4L 和 VGLL3 的过表达是体内 BRAF 抑制剂耐药性的重要驱动因素。此外,我们还介绍了一种新颖的单细胞基因组学分析方法,通过转座子诱变对肿瘤内成千上万的单个细胞进行基因分型。这种方法揭示了异种移植肿瘤中惊人的遗传多样性,并发现了在不同肿瘤亚克隆中出现的反复共存突变。总之,这些观察结果揭示了驱动 BRAF 抑制剂耐药性的未被重视的遗传复杂性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Single-cell genomics analysis reveals complex genetic interactions in an in vivo model of acquired BRAF inhibitor resistance.

The evolution of therapeutic resistance is a major obstacle to the success of targeted oncology drugs. While both inter- and intratumoral heterogeneity limit our ability to detect resistant subpopulations that pre-exist or emerge during treatment, our ability to analyze tumors with single-cell resolution is limited. Here, we utilized a cell-based transposon mutagenesis method to identify mechanisms of BRAF inhibitor resistance in a model of cutaneous melanoma. This screen identified overexpression of NEDD4L and VGLL3 as significant drivers of BRAF inhibitor resistance in vivo. In addition, we describe a novel single-cell genomics profiling method to genotype thousands of individual cells within tumors driven by transposon mutagenesis. This approach revealed a surprising genetic diversity among xenograft tumors and identified recurrent co-occurring mutations that emerge within distinct tumor subclones. Taken together, these observations reveal an unappreciated genetic complexity that drives BRAF inhibitor resistance.

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CiteScore
6.90
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审稿时长
13 weeks
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