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An Lkb1-Sik axis suppresses lung tumor growth and controls differentiation. Cancer discovery Murray, C. W., Brady, J. J., Tsai, M. K., Li, C. n., Winters, I. P., Tang, R. n., Andrejka, L. n., Ma, R. K., Kunder, C. A., Chu, P. n., Winslow, M. M. 2019

Abstract

The kinase, LKB1, is a critical tumor suppressor in sporadic and familial human cancers, yet the mechanisms by which it suppresses tumor growth remain poorly understood. To investigate the tumor-suppressive capacity of four canonical families of Lkb1 substrates in vivo, we employed CRISPR/Cas9-mediated combinatorial genome editing in a mouse model of oncogenic Kras-driven lung adenocarcinoma. We demonstrate that members of the salt-inducible kinase (Sik) family are critical for constraining tumor development. Histological and gene expression similarities between Lkb1- and Sik-deficient tumors suggest that Siks and Lkb1 operate within the same axis. Furthermore, a gene expression signature reflecting Sik deficiency is enriched in LKB1 mutant human lung adenocarcinomas and is regulated by LKB1 in human cancer cell lines. Together, these findings reveal a key Lkb1-Sik tumor-suppressive axis and underscore the need to redirect the focus of efforts to elucidate the mechanisms through which LKB1 mediates tumor suppression.

View details for DOI 10.1158/2159-8290.CD-18-1237

View details for PubMedID 31350327