1. Genome-wide CRISPR screens in spheroid culture reveal that the tumor suppressor LKB1 inhibits growth via the PIKFYVE lipid kinase.
- Author
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Ferrarone, John R., Thomas, Jerin, Unni, Arun M., Yuxiang Zheng, Nagiec, Michal J., Gardner, Eric E., Mashadova, Oksana, Li, Kate, Koundouros, Nikos, Montalbano, Antonino, Mustafa, Meer, Cantley, Lewis C., Blenis, John, Sanjana, Neville E., and Varmus, Harold
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CRISPRS , *MEDICAL screening , *LIPIDS , *PROTEIN kinases , *CHEMICAL inhibitors , *CURCUMIN - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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