LKB1 expressed in dendritic cells governs the development and expansion of thymus-derived regulatory T cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA630661 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11700306.fastq.gz | Fastqsanger.gz | |||
| SRR11700307.fastq.gz | Fastqsanger.gz | |||
| SRR11700308.fastq.gz | Fastqsanger.gz | |||
| SRR11700309.fastq.gz | Fastqsanger.gz | |||
| SRR11700310.fastq.gz | Fastqsanger.gz |
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Project description:Liver Kinase B1 (LKB1) plays a key role in cellular metabolism by controlling AMPK activation. However, its function in dendritic cell (DC) biology has not been addressed. Here, we find that LKB1 functions as a critical brake on DC immunogenicity, and when lost, leads to reduced mitochondrial fitness and increased maturation, migration, and T cell priming of peripheral DCs. Concurrently, loss of LKB1 in DCs enhances their capacity to promote output of regulatory T cells (Tregs) from the thymus, which dominates the outcome of peripheral immune responses, as suggested by increased resistance to asthma and higher susceptibility to cancer in CD11cΔLKB1 mice. Mechanistically, we find that loss of LKB1 specifically primes thymic CD11b+ DCs to facilitate thymic Treg development and expansion, which is independent from AMPK signalling, but dependent on mTOR and enhanced phospholipase C β1-driven CD86 expression. Together, our results identify LKB1 as a critical regulator of DC-driven effector T cell and Treg responses both in the periphery and the thymus.
2020-05-07 | GSE149941 | GEO
Project description:Liver Kinase B1 (LKB1) plays a key role in cellular metabolism by controlling AMPK activation. However, its function in dendritic cell (DC) biology has not been addressed. Here, we find that LKB1 functions as a critical brake on DC immunogenicity, and when lost, leads to reduced mitochondrial fitness and increased maturation, migration, and T cell priming of peripheral DCs. Concurrently, loss of LKB1 in DCs enhances their capacity to promote output of regulatory T cells (Tregs) from the thymus, which dominates the outcome of peripheral immune responses, as suggested by increased resistance to asthma and higher susceptibility to cancer in CD11cΔLKB1 mice. Mechanistically, we find that loss of LKB1 specifically primes thymic CD11b+ DCs to facilitate thymic Treg development and expansion, which is independent from AMPK signalling, but dependent on mTOR and enhanced phospholipase C β1-driven CD86 expression. Together, our results identify LKB1 as a critical regulator of DC-driven effector T cell and Treg responses both in the periphery and the thymus.
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Project description:Germline mutations in LKB1 (STK11) are associated with the Peutz–Jeghers syndrome (PJS), which includes aberrant mucocutaneous pigmentation, and somatic LKB1 mutations occur in 10% of cutaneous melanoma. By somatically inactivating Lkb1 with K-Ras activation (+/- p53 loss) in murine melanocytes, we observed variably pigmented and highly metastatic melanoma with 100% penetrance. LKB1 deficiency resulted in increased phosphorylation of the SRC-family kinase (SFK) YES and the subsequent expansion of a CD24+ cell population which showed increased metastatic behavior in vitro and in vivo relative to isogenic CD24- cells. These results suggest that LKB1 inactivation in the context of RAS activation facilitates metastasis by inducing a SFK-dependent expansion of a pro-metastatic, CD24+ tumor sub-population reference x sample
2012-06-24 | E-GEOD-34866 | biostudies-arrayexpress
Project description:Germline mutations in LKB1 (STK11) are associated with the Peutz–Jeghers syndrome (PJS), which includes aberrant mucocutaneous pigmentation, and somatic LKB1 mutations occur in 10% of cutaneous melanoma. By somatically inactivating Lkb1 with K-Ras activation (+/- p53 loss) in murine melanocytes, we observed variably pigmented and highly metastatic melanoma with 100% penetrance. LKB1 deficiency resulted in increased phosphorylation of the SRC-family kinase (SFK) YES and the subsequent expansion of a CD24+ cell population which showed increased metastatic behavior in vitro and in vivo relative to isogenic CD24- cells. These results suggest that LKB1 inactivation in the context of RAS activation facilitates metastasis by inducing a SFK-dependent expansion of a pro-metastatic, CD24+ tumor sub-population
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Project description:LKB1-deficient and LKB1-reconstituted A549 NSCLC cells
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Project description:Mutations in STK11/LKB1 in non-small cell lung cancer (NSCLC) are associated with poor patient responses to immune checkpoint blockade (ICB) and introduction of a Stk11/Lkb1 (L) mutation into murine lung adenocarcinomas driven by mutant Kras and Trp53 loss (KP) resulted in an ICB refractory syngeneic KPL tumor. Mechanistically this occurred because KPL mutant NSCLCs lacked TCF1-expressing CD8 T cells, a phenotype recapitulated in human STK11/LKB1 mutant NSCLCs. Systemic inhibition of Axl results in increased type I interferon secretion from dendritic cells that expanded tumor-associated TCF1+ PD-1+ CD8 T cells, restoring therapeutic response to PD-1 ICB for KPL tumors. This was observed in syngeneic immunocompetent mouse models and in humanized mice bearing STK11/LKB1 mutant NSCLC human tumor xenografts. NSCLC patients with identified STK11/LKB1 mutations receiving bemcentinib and pembrolizumab demonstrated objective clinical response to combination therapy. We conclude that AXL is a critical targetable driver of immune suppression in STK11/LKB1 mutant NSCLC.
2022-01-24 | GSE194166 | GEO
Project description:Gene expression in wildtype mouse stomach wall (n=6), Lkb1+/- mouse stomach wall (n=6) and Lkb1+/- mouse gastric polyps
2010-10-06 | E-MEXP-2444 | biostudies-arrayexpress
Project description:LKB1 encodes a Ser/Thr kinase and acts as an evolutionarily conserved sensor of cellular energy status in eukaryotic cells. LKB1 functions as the major upstream kinase to phosphorylate AMPK and 12 other AMPK-related kinases, which is required for their activation in many cellular contexts. Once activated, AMPK and AMPK-related kinases phosphorylate a diverse array of downstream effectors to switch on ATP-generating catabolic processes and switch off ATP-consuming anabolic processes, thus restoring energy balance during periods of energetic stress. To study the role and mechanisms of Lkb1 in the regulation of hematopoietic stem cell (HSC) biology, we performed transcriptome analysis of sorted LSK (Lin-, Sca-1+, c-Kit+) cells from Lkb1 WT and KO bone marrows at 1 day post-completing tamoxifen injection (DPI). To identify more proximal molecular effects, we chose 1 DPI due to the modest phenotypes in Lkb1 KO mice, yet documentation of efficient Lkb1 deletion in LSK cells at this very early time point. We treated Lkb1 L/L rosa26CreERT2 and Lkb1 L/L mice (C57BL/Ka-CD45.2:Thy-1.1 background) with Tamoxifen for 5 days to somatically delete Lkb1 in adult mice, and generated Lkb1 WT and KO mice. At 1 DPI, we prepared single-cell suspensions from bone marrow (from femoral and tibial bones), and stained and sorted LSK populations using FACSAria (Becton Dickinson, Mountain View, CA). The RNA was extracted from sorted LSK cells, amplified and subjected to gene profiling. The samples include 3 Lkb1 WT (Lkb1 WT 5-7) and 4 Lkb1 KO (Lkb1 KO 4-7) replicates.
2010-12-01 | E-GEOD-24765 | biostudies-arrayexpress
Project description:Inherited mutation in LKB1 results in the Peutz-Jeghers syndrome (PJS), characterized by intestinal hamartomas and a modestly increased frequency of gastrointestinal and breast cancer1. Somatic inactivation of LKB1 occurs in human lung adenocarcinoma2-4, but its tumor suppressor role in this tissue is unknown. Here we show that somatic Lkb1 deficiency strongly cooperates with somatic K-rasG12D activating mutation to accelerate the development of mouse lung tumorigenesis. Lkb1 deficiency in the setting of K-rasG12D mutation (K-ras Lkb1L/L) was associated with decreased tumor latency and increased tumor aggressiveness including metastasis. Furthermore, tumors from K-ras Lkb1L/L mice demonstrated histologies--squamous, adenosquamous and large cell--not seen with K-rasG12D mutation, Ink4a/Arf inactivation, or p53 inactivation alone or in combination. Experiments in vitro suggest that LKB1 suppresses lung tumorigenesis and progression through both p16INK4a-ARF-p53 dependent and independent mechanisms. These data indicate that LKB1 regulates lung tumor progression and differentiation. Keywords: cancer research To analyze the role of LKB1 in lung cancer progression and differentiation, we have dissected the lung tumors from mice with/without lkb1 loss and performed the microarray analyses to compare their gene expression pattern. In addition, we have also performed microarray analysis in both A549 and H2126 cell lines after reconsistitution of either wt-lkb1 or the kinase dead form of lkb1 (lkb1-KD) to confirm what we observed from in vivo studies.
2007-08-28 | E-GEOD-6135 | biostudies-arrayexpress
Project description:Like all organs, the thymus grows in size and function rapidly during development, which comes to a halt after birth. However, the molecular mechanisms behind such a transition in the thymus remain obscure. Using single-cell RNA sequencing (scRNA-seq) of the murine thymic stroma, we identified that major transcriptomic changes occur in the endothelium and mesenchyme across the transition to homeostasis. Differentially expressed gene and intercellular network analyses of temporally resolved scRNA-seq data revealed fibroblast-derived insulin-like growth factor 2 (IGF2) as a candidate driving neonatal thymic expansion. We demonstrated IGF2 activity promotes a cortical TEC-specific proliferation and is tightly regulated at the thymic growth transition. Bulk RNA-seq of human thymi across the transition also revealed IGF2 to drive thymic expansion, suggesting an evolutionarily conserved role. Our study highlights the role of a fibroblast-derived IGF2 in promoting cTEC proliferation, resulting in early thymic expansion that is followed by down-regulation to establish homeostasis.
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