biostudies-literatureMurray CWTRDRPNHGRI NIH HHSNCI NIH HHSNIHDamon Runyon Cancer Research FoundationNIH HHS1590-1605https://www.ebi.ac.uk/biostudies/studies/S-EPMC6825558biostudies-literatureUnknown9(11)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 <i>in vivo</i>, we used CRISPR/Cas9-mediated combinatorial genome editing in a mouse model of oncogenic KRAS-driven lung adenocarcinoma. We demonstrate that members of the SIK family are critical for constraining tumor development. Histologic 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 <i>LKB1</i>-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 efforts to elucidate the mechanisms through which LKB1 mediates tumor suppression. SIGNIFICANCE: Uncovering the effectors of frequently altered tumor suppressor genes is critical for understanding the fundamental driving forces of cancer growth. Our identification of the SIK family of kinases as effectors of LKB1-mediated tumor suppression will refocus future mechanistic studies and may lead to new avenues for genotype-specific therapeutic interventions.<i>This article is highlighted in the In This Issue feature, p. 1469</i>.Cancer discoveryAn LKB1-SIK Axis Suppresses Lung Tumor Growth and Controls Differentiation.PMC682555827FT-0044R01-CA175336R01-CA207133S10OD018220F31-CA210627R01-CA230919P30 CA124435R01 CA175336S10 OD018220F32 CA189659F31 CA210627R01 CA207133P30-CA124435DRG-2331NIH T32-HG000044R01 CA230919F32-CA189659T32 HG000044Winslow MMChu PLi CWinters IPMurray CWBrady JJTsai MKAndrejka LTang RKunder CAMa RKfalseAn 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 <i>in vivo</i>, we used CRISPR/Cas9-mediated combinatorial genome editing in a mouse model of oncogenic KRAS-driven lung adenocarcinoma. We demonstrate that members of the SIK family are critical for constraining tumor development. Histologic 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 <i>LKB1</i>-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 efforts to elucidate the mechanisms through which LKB1 mediates tumor suppression. SIGNIFICANCE: Uncovering the effectors of frequently altered tumor suppressor genes is critical for understanding the fundamental driving forces of cancer growth. Our identification of the SIK family of kinases as effectors of LKB1-mediated tumor suppression will refocus future mechanistic studies and may lead to new avenues for genotype-specific therapeutic interventions.<i>This article is highlighted in the In This Issue feature, p. 1469</i>.2019-01-01T00:00:00Z2019 Nov2024-02-15T22:00:40.848Z2020-10-29T10:06:53ZS-EPMC68255583135032710.1158/2159-8290.CD-18-123710.1158/2159-8290.cd-18-1237