Genome- wide CRISPR screens in spheroid culture reveal that the tumor suppressor LKB1 inhibits growth via the PIKFYVE lipid kinase

• 成果类型: Article
• 署名作者: Ferrarone, John R.; Thomas, Jerin; Unni, Arun M.; Zheng, Yuxiang; Nagiec, Michal J.; Gardner, Eric E.; Mashadova, Oksana; Li, Kate; Koundouros, Nikos; Montalbano, Antonino; Mustafa, Meer; Cantley, Lewis C.; Blenis, John; Sanjana, Neville E.; Varmus, Harold
• 署名单位: Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; New York University; Cornell University; Weill Cornell Medicine; Northwell Health; Hofstra University; Harvard University; Harvard Medical School; Regeneron; 23andMe, Inc.
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11869
• DOI: 10.1073/pnas.2403685121
• 发表日期: 2024-05-21
• 关键词: cancer; TRAFFICKING; target; pi(3; 5)p-2; apilimod; PATHWAY

摘要

The tumor suppressor LKB1 is a serine/threonine protein kinase that is frequently mutated in human lung adenocarcinoma (LUAD). LKB1 regulates a complex signaling network that is known to control cell polarity and metabolism; however, the pathways that mediate the tumor - suppressive activity of LKB1 are incompletely defined. To identify mechanisms of LKB1mediated growth suppression, we developed a spheroid - based cell culture assay to study LKB1dependent growth. We then performed genome - wide CRISPR screens in spheroidal culture and found that LKB1 suppresses growth, in part, by activating the PIKFYVE lipid kinase. Finally, we used chemical inhibitors and a pH - sensitive reporter to determine that LKB1 impairs growth by promoting the internalization of wild - type EGFR in a PIKFYVE - dependent manner.