Nat Genet:CRISPR与DNA条形码 “联姻”,追踪癌症发展

2018-04-08 忐忑 生物探索

CRISPR作为一项基因编辑新技术,已在生物学中得到了广泛应用。现在,斯坦福大学的科学家找了一个新方法——将CRISPR/Cas9与DNA条形码技术联合起来,可以修饰小鼠的肺部中与癌症相关的基因,并能精确追踪肿瘤的单个细胞。这一“强强联合”或将显著加速癌症研究和药物开发。

CRISPR作为一项基因编辑新技术,已在生物学中得到了广泛应用。现在,斯坦福大学的科学家找了一个新方法——将CRISPR/Cas9与DNA条形码技术联合起来,可以修饰小鼠的肺部中与癌症相关的基因,并能精确追踪肿瘤的单个细胞。这一“强强联合”或将显著加速癌症研究和药物开发。


来源: Courtesy Monte Winslow

该研究的资深作者、斯坦福大学医学院的遗传学家Monte Winslow说道,“人类癌症并不只是因为一个肿瘤抑制基因的突变,而且存在多种突变组合。但问题是,这些不同的突变基因是如何合作的?”

就在几年前,这种图谱研究是一项耗费巨大、历时数年的工作。研究人员需要培育多种不同谱系的遗传修饰小鼠,每只小鼠都携带有不同的失活肿瘤抑制基因。为了探索所有可能的组合,研究人员需要构建成百上千只的小鼠模型。

相比之下,Winslow和他的同事在几个月之内就完成了相关实验,只用了不到24只小鼠。 “我们详细分析了小鼠肺癌基因型的情况,远超过去15年该领域所进行的研究。” Winslow强调道。相关 研究结果发表在《Nature Genetics》杂志上。

1.一个疯狂的想法

研究小组利用CRISPR-Cas9这个强大的基因编辑工具,就可以轻易地替换、修改或删除生物体内的基因序列,从而在单个动物的肺中创造出多种基因不同的肿瘤。Winslow说,“我们可以在一只老鼠身上诱发成千上万的克隆肿瘤。”

然而,为了得出关于不同基因突变组合效应的有用结论,科学家需要一种精确的方法来标记追踪不同肿瘤的生长。在这里,传统的技术是不够的,包括尝试切除和比较个体肿瘤的大小。

而最新的解决方案其实来自于斯坦福大学的进化生物学家Dmitri Petrov的一个疯狂想法。Dmitri Petrov是这项新研究的资深作者,他曾与斯坦福大学的物理学家Daniel Fisher和遗传学家Gavin Sherlock合作开发了DNA条码,作为研究酵母快速进化的一种方法。当Petrov了解到Winslow的实验时,他想DNA条码这项技术或许可以应用在小鼠身上。

Winslow 最初听闻这个想法,还有所顾虑。“Petrov是那种有很多疯狂想法的人,起初,我们并不认为他的想法可行。后来,我们认为或许值得一试。” Winslow说道。

2.计算条形码

Petrov的想法是,将短的、独特的DNA序列黏附于小鼠肺内的单个肿瘤细胞。每一个序列的功能就像是遗传条码,当每个癌细胞扩增时,条码的数量会随之增加。

现在,科学家们不必煞费苦心地切除单个肿瘤,而是将整个癌肺取出,然后用高通量的DNA测序和计算分析来精确的确定肿瘤的大小,计算条形码出现的频率。通过分析不同的条码,科学家可以比以前更精确地比较肿瘤的大小。

Petrov说,“我们现在可以在同一个小鼠身上产生大量具有特定遗传特征的肿瘤,并在规模和精度上分别跟踪它们的生长。”

3.遗传多样性

CRISPR-Cas9和DNA条形码的结合,可以让科学家在实验室中复制癌症患者机体中所观察到的遗传多样性,也克服了科学家对癌症复杂性的恐惧心理。

Winslow说,几十年来,我们一直知道人类的肿瘤非常复杂,而且因人而异,如何能够真正地重建它,以便能够研究它?如今,在CRISPR/Cas9与DNA条形码技术的结合下,我们可以同时模拟30种不同的癌症遗传变异。

这项研究还有一个惊人的发现——许多肿瘤抑制基因都是与环境相关的,也就是说,当另外一个基因存在或缺失时仅会影响肿瘤的生长 。“我们现在处于一个很好的位置,可以理解关键的癌症驱动基因是如何相互作用的,以及为什么携带相同突变的肿瘤有时会进展迅速,有时却不会。” 研究的第一作者Christopher McFarland说,他是Petrov实验室的博士后学者。

这项组合技术对癌症药物测试或许也有帮助,制药公司可以同时检测数千种肿瘤变异的药物,以观察哪些药物对治疗有反应,哪些药物没有反应。

“我们可以帮助理解为什么靶向疗法和免疫疗法有时在病人身上效果很好,有时却会失败。” Petrov说,“我们假设肿瘤的遗传异质性可能是部分原因,研究人员希望能够进行更为深入的研究。”

原始出处:Zoë N. Rogers, Christopher D. McFarland, Ian P. Winters, et al. Mapping the in vivo fitness landscape of lung adenocarcinoma tumor suppression in mice. Nature Genetics (2018)

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    2018-04-10 yuandd