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Integrative Single Cell Multiomic Profiling Analysis Reveals HOX-PBX Gene Regulatory Network Regulating the Survival of mTOR Hyperactive Cells [snATAC-Seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE217106 | GEO | 2023/04/03

REPOSITORIES: GEO

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Integrative Single Cell Multiomic Profiling Analysis Reveals HOX-PBX Gene Regulatory Network Regulating the Survival of mTOR Hyperactive Cells [snRNA-Seq]

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

Hyperactive mTORC1 in Lung Mesenchyme Induces Endothelial Cell Dysfunction and Pulmonary Vascular Remodeling

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

Effect of the reduced mTORC1 activity on gene expression in LAM cells

Project description:mTORC1 is inhibited by rapamycin or Torin1 in lymphangioleiomyomatosis (LAM) 621-101 (TSC2-deficient) cells, in which mTORC1 activity is elevated, and we compared these effects to inhibition of S6K and its target SRPK2.

2024-11-20 | GSE273387 | GEO

Whole transcriptome (gene expression and splice isoform changes) profiling using Affymetrix Human Transcriptome Array 2.0

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

Investigation of the gene expression changes triggered by the lung mesenchymal Tsc2KO in each major cell subpopulation of the adult mouse lung

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

Expression data from Tsc2-null cell line ELT3, and the ELT3-derivative rapamycin-resistant cell line ELT3-245

Project description:Tuberous Sclerosis Complex (TSC) and Lymphangioleiomyomatosis (LAM) are caused by inactivating mutations in TSC1 or TSC2, leading to mTORC1 hyperactivation. The mTORC1 inhibitors rapamycin and analogs (rapalogs) are approved for treating of TSC and LAM. Due to their cytostatic and not cytocidal action, discontinuation of treatment leads to tumor regrowth and decline in pulmonary function. Therefore, life-long rapalog treatment is proposed for the control of TSC and LAM lesions, which increases the chances for the development of acquired drug resistance. Understanding the signaling perturbations leading to rapalog resistance is critical for the development of better therapeutic strategies. We developed the first Tsc2-null rapamycin-resistant cell line, ELT3-245, which is highly tumorigenic in mice, and refractory to rapamycin treatment. In vitro ELT3-245 cells exhibit enhanced anchorage-independent cell survival, resistance to anoikis, and loss of epithelial markers. A key alteration in ELT3-245 is increased β-catenin signaling. We propose that a subset of cells in TSC and LAM lesions have additional signaling aberrations, thus possess the potential to become resistant to rapalogs. Alternatively, when challenged with rapalogs TSC-null cells are reprogrammed to express mesenchymal-like markers. These signaling changes could be further exploited to induce clinically-relevant long-term remissions.

2018-09-06 | GSE119524 | GEO

Transcript profiling of Lymphangioleiomyomatosis (LAM) nodules in Human Patients

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

Tissue-Engineered Disease Modeling of Lymphangioleiomyomatosis Exposes a Therapeutic Vulnerability to HDAC Inhibition

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

CEH-60/PBX regulates vitellogenesis and cuticle formation through interaction with UNC-62/MEIS in Caenorhabditis elegans

Project description:The onset of sexual maturity involves dramatic changes in physiology and gene expression in many animals. A textbook example is the production of enormous amounts of yolk proteins destined for the nascent oocytes, termed vitellogenesis. We previously identified the rapidly evolving PBC-class Hox-cofactor CEH-60/PBX as necessary for abundant vit transcription in C. elegans. Differential proteomics data shows that all vitellogenin proteins are indeed drastically downregulated in ceh-60 mutant animals and suggest an additional role for CEH-60’s involvement cuticle structure, innate immunity and stress response.

2019-09-25 | PXD013584 | Pride

Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus Trial (The MILES Trial)

Project description:<p>Lymphangioleiomyomatosis (LAM) is an uncommon, progressive, cystic lung disease that predominantly affects young women. It is believed to be caused by defects within cellular pathways that regulate nutrient uptake, cell size, cell migration, and cell proliferation. The disease is caused by mutations in tuberous sclerosis complex (TSC) genes. Individuals with Lymphangioleiomyomatosis (LAM) often experience pneumothorax and chylothorax, as well progressive loss of lung function. Lymphangioleiomyomatosis (LAM) is frequently fatal and existing therapies for the disease have not proven effective. Lung transplantation can be considered as a last option, but alternative treatments are needed. Sirolimus is an immunosuppressive drug that is often used in people who have had kidney transplants. It directly affects the genetic pathway that causes Lymphangioleiomyomatosis (LAM). This study will evaluate the safety and effectiveness of sirolimus in stabilizing or improving lung function in people with Lymphangioleiomyomatosis (LAM).</p> <p>Individuals interested in participating in this 2-year, double-blind study will first report to the study sites for pulmonary function testing to determine their eligibility for participation. Participants deemed eligible will be randomly assigned to receive either sirolimus or placebo for 1 year. Sirolimus or placebo will be administered in 2 tablet doses (2 mg for sirolimus) for the duration of the study. Study visits will occur at baseline, Week 3, every 3 months for 12 months, and Months 18 and 24. Study visits will include a physical exam, questionnaires, a pregnancy test, blood and urine collection, and functional lung tests. A 6-minute walk test will occur at most study visits; a chest x-ray will be taken at baseline and Month 24; and a volumetric computed tomography scan will occur at baseline Month 12, and Month 24. Adverse events, medication side effects, and lung function will be assessed at each visit.</p>

| phs000605 | dbGaP

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