Genome-wide CRISPR screens of oral squamous cell carcinoma reveal fitness genes in the Hippo pathway.
Genome-wide CRISPR screens of oral squamous cell carcinoma reveal fitness genes in the Hippo pathway.
复制标题
口服鳞状细胞癌的全基因组CRISPR筛选显示河马途径中的适应性基因。
DOI：
10.7554/elife.57761
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发表时间：
2020-09-29
期刊：
影响因子：
7.7
通讯作者：
Cheong SC
中科院分区：
文献类型：
--
作者：
Chai AWY;Yee PS;Price S;Yee SM;Lee HM;Tiong VK;Gonçalves E;Behan FM;Bateson J;Gilbert J;Tan AC;McDermott U;Garnett MJ;Cheong SC
口腔鳞状细胞癌(OSCC)迫切需要新的治疗靶点。我们在21个口腔鳞癌细胞系中进行了全基因组CRISPR-Cas9筛查，这些细胞系主要来自亚洲人，以确定可以探索作为治疗靶点的遗传易感性。我们发现了已知的和新的适合性基因，并证明了许多先前发现的与口腔鳞癌相关的癌症基因是非必需的，可能具有有限的治疗价值，而其他适合性基因值得进一步研究它们作为治疗靶点的潜力。我们验证了对河马途径的YAP1和WWTR1的独特依赖性，其中一个Paralog的适应性损失效应只能在一小部分线路中得到补偿。我们还发现，具有WWTR1依赖签名的口腔鳞状细胞与免疫治疗有利反应的生物标志物显著相关。综上所述，我们描绘了口腔鳞癌的遗传脆弱性，使进一步探索的治疗靶点得以优先，包括YAP1和WWTR1的靶点。许多类型的癌症现在都有“靶向治疗”，特别是针对癌细胞赖以生存的基因。但对于最常见的口腔癌-口腔鳞状细胞癌-可用的这些治疗方法很少，每年约有35万人被诊断患有这种癌症。设计有针对性的治疗依赖于对癌细胞基因构成的详细了解。但是，人们对哪些基因导致口腔鳞状细胞癌知之甚少，特别是在生活在亚洲的患者中，那里每年有超过一半的病例被诊断出来。解决这一问题的一种方法是使用基因编辑技术来寻找癌细胞生存所需的基因。现在，Chai等人。他们使用了一种名为CRISPR的基因编辑工具来检查来自被诊断为口腔鳞状细胞癌的患者的21个细胞系。其中大部分来自亚洲患者，其中一些人有咀嚼槟榔的历史，这会增加患口腔癌的风险。通过逐个地使这些细胞系中的基因失活，Chai等人说。能够识别出918个与癌细胞存活有关的基因。其中一些基因已经与其他类型的癌症的扩散有关，而另一些基因则完全是口腔鳞状细胞癌所特有的。筛查还发现，一些细胞系在没有参与河马信号通路的基因的情况下无法生存，众所周知，河马信号通路与许多其他类型的癌症的进展有关。发现与口腔鳞状细胞癌相关的基因为开发新的靶向治疗开辟了道路。对于这项研究中确定的一些基因，已经存在有针对性的治疗方法，而且有可能改变它们的用途，作为这种普遍存在的口腔癌的治疗方法。但是，考虑到不同的细胞系依靠不同的基因生存，下一步将是确定每个患者的哪些基因要灭活。
New therapeutic targets for oral squamous cell carcinoma (OSCC) are urgently needed. We conducted genome-wide CRISPR-Cas9 screens in 21 OSCC cell lines, primarily derived from Asians, to identify genetic vulnerabilities that can be explored as therapeutic targets. We identify known and novel fitness genes and demonstrate that many previously identified OSCC-related cancer genes are non-essential and could have limited therapeutic value, while other fitness genes warrant further investigation for their potential as therapeutic targets. We validate a distinctive dependency on YAP1 and WWTR1 of the Hippo pathway, where the lost-of-fitness effect of one paralog can be compensated only in a subset of lines. We also discover that OSCCs with WWTR1 dependency signature are significantly associated with biomarkers of favorable response toward immunotherapy. In summary, we have delineated the genetic vulnerabilities of OSCC, enabling the prioritization of therapeutic targets for further exploration, including the targeting of YAP1 and WWTR1. Many types of cancer now have 'targeted treatments', which specifically home in on genes cancer cells rely on for survival. But there are very few of these treatments available for the most common type of mouth cancer, oral squamous cell carcinoma, which around 350,000 people are diagnosed with each year. Designing targeted treatments relies on detailed knowledge of the genetic makeup of the cancer cells. But, little is known about which genes drive oral squamous cell carcinoma, especially among patients living in Asia, which is where over half of yearly cases are diagnosed. One way to resolve this is to use gene editing technology to find the genes that the cancer cells need to survive. Now, Chai et al. have used a gene editing tool known as CRISPR to examine 21 cell lines from patients diagnosed with oral squamous cell carcinoma. Most of these lines were from Asian patients, some of whom had a history of chewing betel quid which increases the risk of mouth cancer. By individually inactivating genes in these cell lines one by one, Chai et al. were able to identify 918 genes linked to the survival of the cancer cells. Some of these genes have already been associated with the spread of other types of cancer, whereas others are completely unique to oral squamous cell carcinoma. The screen also discovered that some cell lines could not survive without genes involved in a signalling pathway called Hippo, which is known to contribute to the progression of many other types of cancer. Uncovering the genes associated with oral squamous cell carcinoma opens the way for the development of new targeted treatments. Targeted therapies already exist for some of the genes identified in this study, and it may be possible to repurpose them as a treatment for this widespread mouth cancer. But, given that different cell lines relied on different genes to survive, the next step will be to identify which genes to inactivate in each patient.