%0 Journal Article
%T Genome-wide CRISPR screens in spheroid culture reveal that the tumor suppressor LKB1 inhibits growth via the PIKFYVE lipid kinase.
%A Ferrarone JR
%A Thomas J
%A Unni AM
%A Zheng Y
%A Nagiec MJ
%A Gardner EE
%A Mashadova O
%A Li K
%A Koundouros N
%A Montalbano A
%A Mustafa M
%A Cantley LC
%A Blenis J
%A Sanjana NE
%A Varmus H
%J Proc Natl Acad Sci U S A
%V 121
%N 21
%D 2024 May 21
%M 38743625
%F 12.779
%R 10.1073/pnas.2403685121
%X 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 LKB1-mediated growth suppression, we developed a spheroid-based cell culture assay to study LKB1-dependent 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.