文章：

系统级综合癌症基因组学的体内功能筛选

In vivo functional screening for systems-level integrative cancer genomics

原文发布日期：2020-07-07

DOI: 10.1038/s41568-020-0275-9

类型: Review Article

开放获取: 否

英文摘要：

With the genetic portraits of all major human malignancies now available, we next face the challenge of characterizing the function of mutated genes, their downstream targets, interactions and molecular networks. Moreover, poorly understood at the functional level are also non-mutated but dysregulated genomes, epigenomes or transcriptomes. Breakthroughs in manipulative mouse genetics offer new opportunities to probe the interplay of molecules, cells and systemic signals underlying disease pathogenesis in higher organisms. Herein, we review functional screening strategies in mice using genetic perturbation and chemical mutagenesis. We outline the spectrum of genetic tools that exist, such as transposons, CRISPR and RNAi and describe discoveries emerging from their use. Genome-wide or targeted screens are being used to uncover genomic and regulatory landscapes in oncogenesis, metastasis or drug resistance. Versatile screening systems support experimentation in diverse genetic and spatio-temporal settings to integrate molecular, cellular or environmental context-dependencies. We also review the combination of in vivo screening and barcoding strategies to study genetic interactions and quantitative cancer dynamics during tumour evolution. These scalable functional genomics approaches are transforming our ability to interrogate complex biological systems.

摘要翻译： 

随着所有主要人类恶性肿瘤的遗传图谱绘制完成，我们接下来面临的挑战是明确突变基因的功能、其下游靶点、相互作用及分子网络。此外，在功能层面尚未得到充分理解的还包括未发生突变但失调的基因组、表观基因组和转录组。操纵性小鼠遗传学研究的突破为探索高等生物疾病发病机制中分子、细胞与系统信号的相互作用提供了新机遇。本文综述了利用遗传扰动和化学诱变技术在小鼠中进行功能筛选的策略，概述了现有转座子、CRISPR及RNAi等遗传工具谱系，并介绍了基于这些工具取得的研究发现。全基因组或靶向筛选技术正被用于揭示肿瘤发生、转移及耐药性过程中的基因组与调控图谱。多功能筛选系统支持在不同遗传和时空背景下进行实验，以整合分子、细胞及环境背景依赖性。我们还探讨了体内筛选与条形码标记策略相结合的研究方法，用于探索肿瘤演化过程中的遗传相互作用和定量癌症动力学。这些可扩展的功能基因组学方法正在重塑我们解析复杂生物系统的能力。

原文链接：

In vivo functional screening for systems-level integrative cancer genomics