An Lkb1-Sik axis suppresses lung tumor growth and controls differentiation

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.