Effect of the reduced mTORC1 activity on gene expression in LAM cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE273387 | GEO | 2024/11/20
REPOSITORIES: GEO
Similar Datasets
Project description:Transcriptome analysis of total RNA samples from human cell line (LAM 621-101, female) Global gene and splice isoform expression profiling was performed to get a comprehensive view of transcriptome changes in human Lymphangioleiomyomatosis (LAM 621-101, female) cell line after inhibition of mTORC1 and SRPK2 proteins.
2017-09-28 | GSE104335 | GEO
Project description:Patients with Lymphangioleiomyomatosis (LAM) develop nodules of cells within the lung parenchyma. These lesions contain both TSC2-/- LAM cells, and wild type fibroblasts. We investigated the effect of TSC2-/- cells on the transcriptional profile of both normal fibroblasts and fibroblasts isolated from LAM patient tissue (LAFs) using Affymetrix Gene Chip arrays, to identify upregulated pathways which could contribute to LAM pathology. We used Affymetrix microarrays to detail the changes in the global profile of gene expression in fibroblasts following co-culture with 621-101 cells, and identified upregulation of several chemokines, indicating that the fibroblasts had adopted an inflammatory phenotype.
2021-12-31 | GSE160618 | GEO
Project description:Lymphangioleiomyomatosis (LAM) is characterized by cystic lung destruction caused by smooth, muscle-like LAM cells which have mutations in the tumor suppressor genes Tuberous Sclerosis Complex (TSC) 1 or 2, and the capacity to metastasize. Since chemokines and their receptors function in chemotaxis of metastatic cells, we hypothesized that LAM cells may be recruited by chemokine(s) in the lung. Quantification of 25 chemokines in bronchoalveolar lavage fluid from LAM patients and healthy volunteers revealed that concentrations of MCP-1/CCL2, GROa/CXCL1 and ENA-78/CXCL5 were significantly higher in samples from LAM patients than healthy volunteers. In this transcript analysis, expression of chemokine and chemokine receptor mRNA in LAM cells differed from those in melanoma and smooth muscle cells. Subsequent immunohistochemistry of lung sections from 30 LAM patients confirmed protein expression of chemokines and these receptors varied among LAM patient and differed from that seen in breast cancer and melanoma cells. . In vitro, MCP-1/CCL2 induced selective migration of cells showing loss of heterozygosity of TSC2 from a heterogeneous populations of cells grown from explanted LAM lungs. In addition, the frequencies of single-nucleotide polymorphisms in the MCP-1 gene promoter region differed significantly in LAM patients and healthy volunteers (p=0.018), and one polymorphism was associated significantly more frequently with the decline of lung function. These observations are consistent with the notion that chemokines such as MCP-1 may serve to specify site of LAM cell metastasis. Keywords: Human patient sample comparison with cell lines The study is of case/control design with biological replication. Biopsies of nodules from 14 LAM patients (cases) are compared with cultured cell lines (controls) with similar properties.
2008-12-30 | E-GEOD-12027 | biostudies-arrayexpress
Project description:To uncover genes regulated by mTORC1 and estradiol in uterine Tsc2-null LAM like cells, we performed RNAseq on uteri from 12-week old wild-type (WT) and uterine-specific Tsc2-null (KO) mice that were either untreated (intact), oopherectomized (ovx) or oopherectomized + treated with 17β-estradiol pellets (E2) for 8 weeks. We identified genes that were both estradiol- and TSC2-mediated. Uterine mRNA profiles of 12 week old wild type (WT) and uterine-specific Tsc2-null (KO) mice in the presence or absence of estradiol were generated using Illumina HiSeq2500
2016-02-26 | E-GEOD-78701 | biostudies-arrayexpress
Project description:Rationale: Increased matrix metalloproteinase (MMP) activity has been implicated in the pathogenesis of lymphangioleiomyomatosis (LAM). Objectives: To investigate how TSC1 or TSC2 deficiency alters MMP expression and regulation. Methods: We studied immortalized cells that lack TSC2 derived from an angiomyolipoma (AML) of a LAM patient, and a TSC2 add back derivative; and murine embryonic fibroblast cells that lack Tsc1 or Tsc2 and respective controls. Global gene expression analysis was carried out in the AML and derivative cell lines. MMP levels in the conditioned media from these cells were analyzed by zymography and ELISA. Measurements and Main Results: We found increased MMP-2 expression in cells lacking TSC1/TSC2 compared to their respective controls by zymography. MMP-2 overproduction by these cells was not affected by rapamycin treatment. Gene expression analysis confirmed increased MMP-2 gene expression that was not affected by rapamycin. Furthermore, multiple other genes were found to be over-expressed in rapamycin-treated TSC2-deficient cells compared to TSC2+ cells. Conclusions: We conclude that TSC1/TSC2 deficiency leads to MMP-2 overproduction that is rapamycin insensitive, and that several genes exhibit similar patterns suggesting TSC1/TSC2 dependent but mTOR independent pathways may be involved in the pathogenesis of LAM.
2009-10-21 | GSE16944 | GEO
Project description:Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease caused by tuberous sclerosis complex 1/2 (TSC1/2) gene mutations resulting in activation of the mechanistic target of rapamycin complex 1 (mTORC1). A subset of LAM patients develops pulmonary vascular remodeling and pulmonary hypertension. To model LAM disease, we utilized an mTORC1 gain-of-function mouse model with a Tsc2 knock-out (Tsc2KO) specific to lung mesenchyme (Tbx4LME-CreTsc2fl/fl), similar to the mesenchyme specific genetic alterations seen in human disease. As early as 8 weeks of age, ECs from Tbx4LME-CreTsc2fl/fl mice exhibited marked transcriptomic changes despite absence of morphological changes to the distal lung microvasculature. In contrast, 1 year old Tbx4LME-CreTsc2fl/fl mice spontaneously developed pulmonary vascular remodeling with increased medial thickness. We subsequently performed single cell RNA-sequencing of 1 year old mouse lung and identified paracrine ligands originating from Tsc2KO mesenchyme impacting arterial endothelial cells. These cells contained transcriptionally altered genes including those in pathways associated with blood vessel remodeling, highlighting the pathogenic importance of the mesenchymal-endothelial cell axis.
2024-01-25 | GSE249634 | GEO
Project description:Lymphangioleiomyomatosis (LAM) is a rare, debilitating lung disease that predominantly affects women of reproductive age. LAM cells carry deleterious mutations of tuberous sclerosis complex (TSC1/TSC2) genes, resulting in hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) and ultimately dysregulated cell growth. The integrative single cell omics data identified the activation of uterine specific HOX-PBX transcriptional programming in pulmonary LAMCORE cells. Network analysis predicted homeobox transcription factors including PBX1 and HOXD11 as key regulators controlling LAMCORE cell fate. Targeting the HOX-PBX network may have therapeutic value in LAM and TSC-related diseases, and possibly in other mTORC1-hyperactive neoplasms.
2023-04-03 | GSE217107 | GEO
Project description:Lymphangioleiomyomatosis (LAM) is a rare, debilitating lung disease that predominantly affects women of reproductive age. LAM cells carry deleterious mutations of tuberous sclerosis complex (TSC1/TSC2) genes, resulting in hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) and ultimately dysregulated cell growth. The integrative single cell omics data identified the activation of uterine specific HOX-PBX transcriptional programming in pulmonary LAMCORE cells. Network analysis predicted homeobox transcription factors including PBX1 and HOXD11 as key regulators controlling LAMCORE cell fate. Targeting the HOX-PBX network may have therapeutic value in LAM and TSC-related diseases, and possibly in other mTORC1-hyperactive neoplasms.
2023-04-03 | GSE217106 | GEO
Project description:Lymphangioleiomyomatosis (LAM) is a rare disease involving cystic lung destruction by invasive LAM cells. These cells harbor loss-of-function mutations in TSC2, conferring hyperactive mTORC1 signaling. Here, tissue engineering tools are employed to model LAM and identify new therapeutic candidates. Biomimetic hydrogel culture of LAM cells is found to recapitulate the molecular and phenotypic characteristics of human disease more faithfully than culture on plastic. A 3D drug screen is conducted, identifying histone deacetylase (HDAC) inhibitors as anti-invasive agents that are also selectively cytotoxic toward TSC2−/− cells. The anti-invasive effects of HDAC inhibitors are independent of genotype, while selective cell death is mTORC1-dependent and mediated by apoptosis. Genotype-selective cytotoxicity is seen exclusively in hydrogel culture due to potentiated differential mTORC1 signaling, a feature that is abrogated in cell culture on plastic. Importantly, HDAC inhibitors block invasion and selectively eradicate LAM cells in vivo in zebrafish xenografts. These findings demonstrate that tissue-engineered disease modeling exposes a physiologically relevant therapeutic vulnerability that would be otherwise missed by conventional culture on plastic. This work substantiates HDAC inhibitors as possible therapeutic candidates for the treatment of patients with LAM and requires further study.
2023-07-06 | GSE179044 | GEO
Project description:Tumor suppressor Tuberous sclerosis complex 2 (TSC2) is a key negative regulator of mammalian target of rapamycin (mTOR), a central controller of cell growth and metabolism in health and disease. Loss of TSC2 induces the constitutive activation of mTORC1 in rare lung disease pulmonary Lymphangioleiomyomatosis (LAM), which affects only women of childbearing age and characterized by lung destruction and progressive loss of pulmonary function. Little is known how TSC2 loss induces LAM and what is the LAM cell of origin. To determine cell-type specific effects of TSC2 loss and mTORC1 activation on lung homeostasis we generated new transgenic mice with targeted Tsc2 deletion in lung mesenchyme Tbx4-Cre+Tsc2flox/flox and lung epithelium Shh-Cre+Tsc2flox/flox. Both Tbx4-Cre+, Tsc2flox/flox and Shh-Cre+, Tsc2flox/flox mice were viable and fertile. Adult Tbx4-Cre+Tsc2flox/flox mice demonstrated mTORC1 activation in lung mesenchyme, progressive alveolar enlargement, female-specific pulmonary function decline and prgenancy-induced lesion growth. To investigate molecular mechanism underlying observed phenotypic changes in the Tsc2KO lungs we performed comparative bulk-RNAseq analysis of the gene expression changes in the major cell subpopulations of the adult female 8-week-old Tsc2KO mouse lungs compared to the age- and sex-matched WT controls.
2020-08-31 | GSE139818 | GEO