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Project description: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-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 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.This article is highlighted in the In This Issue feature, p. 1469.
| S-EPMC6825558 | biostudies-literature
Project description:Background: LKB1 is among the most frequently altered tumor suppressors in lung adenocarcinoma. Despite being implicated in the regulation of a variety of cellular processes, the mechanisms by which LKB1 constrains lung tumor growth and progression remains an area of intense investigation. Purpose: To determine the extent of overlap in terms of the transcriptomic states arising from either Lkb1 deletion or Sik-targeting within cancer cells isolated from genetically engineered mouse models of oncogenic Kras-driven lung adenocarcinoma Approach: Cancer cells sorted from mouse lung tumors of defined genotypes were profiled by RNA-seq. Results: A strong overlap existed between Lkb1-deficient and Sik-targeted cancer cells both at the gene and pathways levels. Conclusions: Given the strong transcriptional overlap, loss of either Lkb1 or Sik appear to be functionally related.
2019-07-05 | GSE133895 | GEO
Project description:Background: LKB1 is among the most frequently altered tumor suppressors in lung adenocarcinoma. Despite being implicated in the regulation of a variety of cellular processes, the mechanisms by which LKB1 constrains lung tumor growth and progression remains an area of intense investigation. Purpose: To assess the impact of CRISPR/Cas9-mediated targeting of the canonical substrates of Lkb1 on tumor size within the context of a genetically engineered mouse model of oncogenic Kras-driven lung adenocarcinoma. Approach: Comparisons of tumor size across genetic perturbations were conducting by measuring tumor sizes via tumor barcode sequencing (Rogers, et al. 2017 Nature Methods). Briefly, tumors were initiated in KrasLSL-G12D/+;R26LSL-Tomato, KrasLSL-G12D/+;Lkb1flox/flox;R26LSL-Tomato;H11LSL-Cas9, and KrasLSL-G12D/+;R26LSL-Tomato;H11LSL-Cas9 mice using a pool of Lenti-sgRNA/Cre vectors that encode a cassette comprised of an sgRNA-specific ID along with clonal identifier. Following, tumor development/progression, the two-component lentiviral cassettes integrated within transduced populations were amplified from genomic DNA extracted from whole lungs homogenates and subjected to next-generation sequencing. From the resulting reads, barcode pileups were generated and filtered prior to translation to absolute numbers of cancer cells via normalization to spiked-in samples of known quantities of cancer cells. The resultant tumor size distribution were then analyzed by multiple statistical measures as described by Rogers, et al. Results: Lkb1 targeting dramatically increased tumor size in the Kras-only setting relative to functionally inert sgRNAs. Unlike other families of Lkb1 substrates, the targeting of the salt inducible kinase (Sik) family increased tumor growth comparable to Lkb1 targeting. In contrast to targeting the paralogs Sik1 and Sik3 individually, dual targeting of Sik1 and Sik3 enhanced tumor growth. Sik targeting in the Lkb1-deficient setting also modestly increased tumor size whereas Lkb1 targeting had no effect. Conclusions: Siks are potent tumor suppressors belonging the family of canonical Lkb1 substrates. Siks retain some tumor-suppressive activity in the absence of Lkb1.
2019-07-03 | GSE133698 | GEO
Project description:An Lkb1-Sik axis suppresses tumor growth and controls differentiation
| PRJNA552908 | ENA
Project description:An Lkb1-Sik axis suppresses tumor growth and controls differentiation [RNA-Seq]
| PRJNA552909 | ENA
Project description:An Lkb1-Sik axis suppresses tumor growth and controls differentiation [Tumor Barcode Sequencing]
| PRJNA552282 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-09-19 | GSE207603 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-04-10 | GSE240595 | GEO
Project description:Obesity-associated metabolic inflammation drives the development of insulin resistance and type 2 diabetes, notably through modulating innate and adaptive immune cells in metabolic organs. The nutrient sensor liver kinase B1 (LKB1) has recently been shown to control cellular metabolism and T cell priming functions of DCs. Here, we report that hepatic DCs from high-fat diet-fed (HFD-fed) obese mice display increased LKB1 phosphorylation and that LKB1 deficiency in DCs (CD11cΔLKB1) worsened HFD-driven hepatic steatosis and impaired glucose homeostasis. Loss of LKB1 in DCs was associated with increased expression of Th17-polarizing cytokines and accumulation of hepatic IL-17A+ Th cells in HFD-fed mice. Importantly, IL-17A neutralization rescued metabolic perturbations in HFD-fed CD11cΔLKB1 mice. Mechanistically, deficiency of the canonical LKB1 target AMPK in HFD-fed CD11cΔAMPKα1 mice recapitulated neither the hepatic Th17 phenotype nor the disrupted metabolic homeostasis, suggesting the involvement of other and/or additional LKB1 downstream effectors. We indeed provide evidence that the control of Th17 responses by DCs via LKB1 is actually dependent on both AMPKα1 salt-inducible kinase signaling. Altogether, our data reveal a key role for LKB1 signaling in DCs in protection against obesity-induced metabolic dysfunctions by limiting hepatic Th17 responses.
| S-EPMC10281441 | biostudies-literature
Project description:The role of STAT2 in mediating the antigrowth effects of type I interferon (IFN) is well-documented in vitro. Yet evidence of IFN-activated STAT2 as having tumor suppressor function in vivo and participation in antitumor immunity is lacking. Here we show in a syngeneic tumor transplantation model that STAT2 reduces tumor growth. Stat2(-/-) mice formed larger tumors compared to wild type (WT) mice. IFN-? treatment of Stat2(-/-) mice did not cause tumor regression. Gene expression analysis revealed a small subset of immunomodulatory genes to be downregulated in tumors established in Stat2(-/-) mice. Additionally, we found tumor antigen cross-presentation by Stat2(-/-) dendritic cells to T cells to be impaired. Adoptive transfer of tumor antigen specific CD8(+) T cells primed by Stat2(-/-) dendritic cells into tumor-bearing Stat2(-/-) mice did not induce tumor regression with IFN-? intervention. We observed that an increase in the number of CD4(+) and CD8(+) T cells in the draining lymph nodes of IFN-?-treated tumor-bearing WT mice was absent in IFN-? treated Stat2(-/-) mice. Thus our study provides evidence for further evaluation of STAT2 function in cancer patients receiving type I IFN based immunotherapy.
| S-EPMC4199898 | biostudies-literature