Analysis of CRISPR-Cas9 screens identifies genetic dependencies in melanoma.
Analysis of CRISPR-Cas9 screens identifies genetic dependencies in melanoma.
复制标题
DOI：
10.1111/pcmr.12919
复制
发表时间：
2021-01
影响因子：
4.3
通讯作者：
Doorn RV
中科院分区：
文献类型：
--
作者：
Christodoulou E;Rashid M;Pacini C;Droop A;Robertson H;Groningen TV;Teunisse AFAS;Iorio F;Jochemsen AG;Adams DJ;Doorn RV
靶向MAPK信号通路已经改变了转移性黑色素瘤的治疗。CRISPR-Cas9基因筛选提供了一种全基因组方法，以发现可能作为治疗靶点的新型遗传依赖性。在这里，我们分析了最近报道的CRISPR-Cas9筛选，比较了来自28种黑色素瘤细胞系和313种其他肿瘤类型细胞系的数据，以确定与黑色素瘤相关的适应性基因。我们在每个黑色素瘤细胞系中发现了平均1,494个适应性基因。我们确定了33个基因，失活的，其中专门减少黑色素瘤的健身。这组肿瘤类型特异性基因包括已建立的黑色素瘤适应性基因以及许多以前与黑色素瘤生长无关的基因。几种基因编码的蛋白质可以使用可用的抑制剂靶向。我们证实了DUSP 4和PPP 2 R2 A的基因失活降低了黑色素瘤细胞的增殖。DUSP 4编码ERK的抑制剂，这表明通过其损失进一步激活MAPK信号传导活性对黑色素瘤细胞选择性有害。总的来说，这些数据提供了黑色素瘤遗传依赖性的资源，可以作为潜在的治疗靶点进行探索。
Targeting the MAPK signaling pathway has transformed the treatment of metastatic melanoma. CRISPR‐Cas9 genetic screens provide a genome‐wide approach to uncover novel genetic dependencies that might serve as therapeutic targets. Here, we analyzed recently reported CRISPR‐Cas9 screens comparing data from 28 melanoma cell lines and 313 cell lines of other tumor types in order to identify fitness genes related to melanoma. We found an average of 1,494 fitness genes in each melanoma cell line. We identified 33 genes, inactivation of which specifically reduced the fitness of melanoma. This set of tumor type‐specific genes includes established melanoma fitness genes as well as many genes that have not previously been associated with melanoma growth. Several genes encode proteins that can be targeted using available inhibitors. We verified that genetic inactivation of DUSP4 and PPP2R2A reduces the proliferation of melanoma cells. DUSP4 encodes an inhibitor of ERK, suggesting that further activation of MAPK signaling activity through its loss is selectively deleterious to melanoma cells. Collectively, these data present a resource of genetic dependencies in melanoma that may be explored as potential therapeutic targets.
登录
查看更多内容
影响因子：
4.6
作者：
Metzakopian E;Strong A;Iyer V;Hodgkins A;Tzelepis K;Antunes L;Friedrich MJ;Kang Q;Davidson T;Lamberth J;Hoffmann C;Davis GD;Vassiliou GS;Skarnes WC;Bradley A
通讯作者：
Bradley A
影响因子：
14.9
作者：
Kuleshov MV;Jones MR;Rouillard AD;Fernandez NF;Duan Q;Wang Z;Koplev S;Jenkins SL;Jagodnik KM;Lachmann A;McDermott MG;Monteiro CD;Gundersen GW;Ma'ayan A
通讯作者：
Ma'ayan A
影响因子：
4
作者：
Christodoulou, Eirini;van Doorn, Remco;Gruis, Nelleke
通讯作者：
Gruis, Nelleke
影响因子：
4.8
作者：
Martina, Jose A.;Puertollano, Rosa
通讯作者：
Puertollano, Rosa
影响因子：
56.9
作者：
Blomen, Vincent A.;Majek, Peter;Brummelkamp, Thijn R.
通讯作者：
Brummelkamp, Thijn R.