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

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

  • Proc Natl Acad Sci U S A. 2024 May 21;121(21):e2403685121. doi: 10.1073/pnas.2403685121.
John R Ferrarone 1 2,  Jerin Thomas 1,  Arun M Unni 1,  Yuxiang Zheng 1,  Michal J Nagiec 1 3,  Eric E Gardner 1,  Oksana Mashadova 1,  Kate Li 1,  Nikos Koundouros 1 3,  Antonino Montalbano 4 5,  Meer Mustafa 4 5,  Lewis C Cantley 1 6,  John Blenis 1 3,  Neville E Sanjana 4 5,  Harold Varmus 1 6
Affiliations

Affiliations

  • 1 Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021.
  • 2 Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY 10021.
  • 3 Department of Pharmacology, Weill Cornell Medicine, New York, NY 10021.
  • 4 New York Genome Center, New York, NY 10013.
  • 5 Department of Biology, New York University, New York, NY 10003.
  • 6 Department of Medicine, Weill Cornell Medicine, New York, NY 10021.
PMID: 38743625 DOI: 10.1073/pnas.2403685121
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.

Keywords

EGFR; LKB1; PIKFYVE; STK11.

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