近日,美国斯坦福大学医学院Michael C. Bassik、Kyuho Han等研究人员合作利用肿瘤球状体CRISPR筛选鉴定出肿瘤3D生长中特有的弱点。这一研究成果于2020年3月11日在线发表在《自然》杂志上。
Title: CRISPR screens in cancer spheroids identify 3D growth-specific vulnerabilities
Author: Kyuho Han, Sarah E. Pierce, Amy Li, Kaitlyn Spees, Grace R. Anderson, Jose A. Seoane, Yuan-Hung Lo, Michael Dubreuil, Micah Olivas, Roarke A. Kamber, Michael Wainberg, Kaja Kostyrko, Marcus R. Kelly, Maryam Yousefi, Scott W. Simpkins, David Yao, Keonil Lee, Calvin J. Kuo, Peter K. Jackson, Alejandro Sweet-Cordero, Anshul Kundaje, Andrew J. Gentles, Christina Curtis, Monte M. Winslow, Michael C. Bassik
Issue&Volume: 2020-03-11
Abstract: Cancer genomics studies have identified thousands of putative cancer driver genes1. Development of high-throughput and accurate models to define the functions of these genes is a major challenge. Here we devised a scalable cancer-spheroid model and performed genome-wide CRISPR screens in 2D monolayers and 3D lung-cancer spheroids. CRISPR phenotypes in 3D more accurately recapitulated those of in vivo tumours, and genes with differential sensitivities between 2D and 3D conditions were highly enriched for genes that are mutated in lung cancers. These analyses also revealed drivers that are essential for cancer growth in 3D and in vivo, but not in 2D. Notably, we found that carboxypeptidase D is responsible for removal of a C-terminal RKRR motif2 from the α-chain of the insulin-like growth factor 1 receptor that is critical for receptor activity. Carboxypeptidase D expression correlates with patient outcomes in patients with lung cancer, and loss of carboxypeptidase D reduced tumour growth. Our results reveal key differences between 2D and 3D cancer models, and establish a generalizable strategy for performing CRISPR screens in spheroids to reveal cancer vulnerabilities.
DOI: 10.1038/s41586-020-2099-x
Source: https://www.nature.com/articles/s41586-020-2099-x
Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html
本期文章:《自然》:Online/在线发表