IL-17 links the tumor suppressor LKB1 to gastrointestinal inflammation and polyposis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1107138 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28878100_1.fastq.gz | Fastqsanger.gz | |||
| SRR28878100_2.fastq.gz | Fastqsanger.gz | |||
| SRR28878101_1.fastq.gz | Fastqsanger.gz | |||
| SRR28878101_2.fastq.gz | Fastqsanger.gz | |||
| SRR28878102_1.fastq.gz | Fastqsanger.gz |
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Project description:Loss-of-function mutations in the tumor suppressor liver kinase B1 (LKB1) promote the development of Peutz-Jeghers Syndrome (PJS), a chronic disease characterized by the development of gastrointestinal (GI) polyps. Treatment options for patients are extremely limited due to a poor understanding of how LKB1 mutations lead to the development of GI polyps. Here, we reveal a role for CREB-regulated transcription coactivator 2 (CRTC2) signaling in the regulation of inflammatory potential in LKB1 mutant T cells. We also demonstrate that targeting CRTC2 and pathogenic T helper 17 (Th17) cells reduces GI polyp growth in LKB1 mutant mice. Our data reveal a critical role for CRTC2 in LKB1-mediated T cell inflammatory responses that we hypothesize predisposes PJS patients harboring LKB1 mutations to GI polyp development.
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Project description:Germline mutations in LKB1 predispose to hereditary Peutz-Jeghers Syndrome (PJS), manifesting with gastrointestinal polyposis. We discovered that conditional deletion of Lkb1 in stromal fibroblasts using Fsp1-Cre leads to expansion of stromal cells and gastrointestinal polyposis in mice. Here we have investigated gene expression signatures in the Fsp1-Cre;Lkb1fl/fl mouse polyps harbouring bi-allelic deletion of Lkb1 in stromal cells together with wild-type epithelium. We provide RNA-seq gene expression data of 6 polyps, 4 adjacent gastric mucosa samples and 5 wild-type gastric mucosa samples from littermate controls. Our experiment demonstrates e.g. activated cytokine signaling and inflammatory pathways in the polyps.
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Project description:Numerous studies have showed that mesenchymal-specific Lkb1 is sufficient for the development of PJS-like polyps in mice. However, the cellular origin and component of these Lkb1-associated polyps and underlying mechanisms remain elusive. In this present study, we generated tamoxifen-inducible Lkb1flox/flox;Myh11-Cre/ERT2 mice and performed scRNA-seq to investigate the cellular complexity of gastrointestinal polyps associated with PJS.
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Project description:Heterozygous germ-line mutations in the LKB1 (STK11) gene cause Peutz-Jeghers syndrome (PJS), an autosomal dominant disorder characterized by hamartomatous polyposis of the gastrointestinal tract and an increased risk of colorectal, breast, ovarian, testicular and cervical cancer. To model the effects of LKB1 mutation in mammary tumourigenesis, we have used a conditional gene targeting strategy to generate a mouse in which exons 4-7 of the Lkb1 gene encoding the kinase domain of the protein are deleted specifically in the mammary gland. Mammary gland tumours arise in these mice with a latency of 46-85 weeks and occur in the thoracic or inguinal glands. These mammary gland tumours were characterised as Grade 2 invasive ductal carcinomas or solid papillary carcinomas and resemble those arising in PJS patients. This mouse model of Lkb1 deficiency provides a potentially useful tool to investigate the role of Lkb1 in tumourigenesis and to guide the development of therapeutic approaches
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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.
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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
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Project description:Excessive hepatic glucose production is a major contributor to the hyperglycemia observed in Type 2 diabetes mellitus. It is widely accepted that it is due to an increase in hepatic gluconeogenesis. While much attention has been devoted to the transcriptional regulation of key gluconeogenic enzymes, much less is known about the regulation of amino acid catabolism that provides gluconeogenic substrates. Here, we emphasize a novel role of LKB1 in this regulation. We show that mice with a hepatocyte-specific deletion of Lkb1 have increased hepatic amino acid catabolism for gluconeogenesis. This occurred during fasting, as well as during the postprandial period, identifying Lkb1 as a critical suppressor of hepatic postprandial gluconeogenesis. Hepatic Lkb1 deletion was also associated with severe alterations in whole body metabolism leading to decreased lean body mass deposition on MRI analysis and, at a longer term, cachexia and sarcopenia as a consequence of the diversion of amino acids for liver metabolism at the expense of muscle. Using genetic and pharmacological approaches, we identified the aminotransferases and Agxt and as critical effectors of the suppressor function of Lkb1 in amino acid-driven gluconeogenesis.
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