An LKB1–SIK Axis Suppresses Lung Tumor Growth and Controls Differentiation

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 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-defi cient tumors suggest that SIKs and LKB1 operate within the same axis. Furthermore, a gene-expression signature refl ecting SIK defi ciency is enriched in LKB1 -mutant human lung adenocarcinomas and is regulated by LKB1 in human cancer cell lines. Together, these fi ndings 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 identifi cation 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-specifi c therapeutic interventions.

Genetic manipulation of LKB1 elicits lethal metastatic prostate cancer

“…It is worth noting that the low number of specimens with alterations in these genes precluded a more conclusive result. The potential involvement of SIK3 in the prostate tumor–suppressive activity of LKB1 is coherent with recent reports in non–small cell lung cancer (Hollstein et al, 2019; Murray et al, 2019), in turn suggesting that the LKB1-SIK tumor suppressive axis might be relevant in different cancer types.…”

Quantitativein vivoanalyses reveal a complex pharmacogenomic landscape in lung adenocarcinoma

“…Previous Tuba-seq analyses focused on comparing the sizes of tumors of different genotypes within individual mice 14, 30 . Such analyses are largely robust to multiple sources of variation among mice such as (1) variation in the efficiency of viral delivery and the resulting differences in tumor number and total tumor burden across mice and (2) variation in the library sequencing depth (each sgID within a mouse is part of the same DNA library reaction).…”

The potent roles of salt-inducible kinases (SIKs) in metabolic homeostasis and tumorigenesis

“…42 Another research reported that KT;H11 LSL-Cas9 (Kras LSL-G12D/+ ;R26 LSL-Tomato ; H11 LSL-Cas9 ) mice with each double or triple Lenti-sgRNA/Cre vector were applied to NSCLC research. 43 They found KT;H11 LSL-Cas9 mice with sgSIK1/3 displayed larger tumor size.…”

“…As such, SIK1 and SIK3 have been revealed as the predominant downstream targets of LKB1 in mediating anti-tumorigenesis effect in NSCLC. 42,43 While some studies provided that SIK2 underwent autophosphorylation and activation in vitro independent on the presence of LKB1. 7 Therefore, whether other members of AMPK subfamily mediating LBK1 functions in metabolic homeostasis and tumorigenesis need more investigations, especially in combination with their conditional KO mouse models.…”

“…7,44 In the absence of LKB1, there is still a residual activation of SIK1, which may be due to the activation by CaMK. 42,43 Phospholipase C (PLC) can boost Ca 2+ influx from endoplasmic reticulum (ER) to the cytoplasm via inositol triphosphate (IP3) receptor, thus activating the CaMK, which leads to the phosphorylation and activation of SIK2 at Ser358. 7,45 PKA can also phosphorylate SIK2 at Ser358.…”