Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA117303 | ENA |
REPOSITORIES: ENA
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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: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
Project description:Syk inhibitor demonstrates antiproliferative effect on Tsc2-deficient cells and LAM lung nodules similar to rapamycin. A feedback loop between Syk inhibition and mTORC1 inhibition pathways is also present in these Tsc2-deficient cells. We used microarrays to discern the potential difference in Syk inhibition and mTORC1-inhibition pathways. The goal was to investigate regulatory pathways or targets of Syk inhibition to induce cytocidal response in Tsc2-deficient cells, independent of its crosstalk with mTORC1 signaling.
2022-02-14 | GSE183110 | GEO
Project description:LAM is a rare disease which causes lung cysts and respiratory failure. TSC2 deficient ‘LAM cells’ with dysregulated mTOR signalling form nodules with fibroblasts causing lung injury. We examined if mTOR dysregulation could induce senescence and impair responses to lung injury. Senescence markers p21 and p16 were increased in LAM lungs and co-localised with alveolar type 2 cells. The SenMayo senescence gene panel was upregulated in LAM alveolar type 2 cells with senescence supressed by mTOR inhibition in patients. LAM cell / fibroblast spheroid cultures induced senescence markers in alveolar type 2 cell organoids, altered their growth and delayed epithelial scratch wound repair. Upstream regulator analysis predicted alveolar type 2 cell IL6 receptor activation. IL6 was produced by LAM cells, was overexpressed in LAM serum and related to lung function, induced p16 and p21 in alveolar type 2 cells and inhibited epithelial wound resolution. Wound repair in the presence of TSC2 null but not TSC2 addback LAM cell / fibroblast spheroids was enhanced by the IL6 receptor antagonist Tocilizumab. Our findings show TSC2 loss induces senescence and IL6 production which are associated with impaired lung repair. Targeting IL6 signalling in parallel with mTOR inhibition, may reduce lung damage in LAM.
2025-08-05 | GSE265851 | 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: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
Project description:Mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is a critical regulator of cell growth by integrating multiple signals (nutrients, growth factors, energy and stress) and is frequently deregulated in many types of cancer. We used a robust experimental paradigm involving the combination of two interventions, one genetic and one pharmacologic to identify genes regulated transcriptionally by mTORC1. In Tsc2+/+, but not Tsc2-/- immortalized mouse embryo fibroblasts (MEFs), serum deprivation downregulates mTORC1 activity. In Tsc2-/- cells, abnormal mTORC1 activity can be downregulated by treatment with rapamycin (sirolimus). By contrast, rapamycin has little effect on mTORC1 in Tsc2+/+ cells in which mTORC1 is already inhibited by low serum. Thus, under serum deprived conditions, mTORC1 activity is low in Tsc2+/+ cells (untreated or rapamycin treated), high in Tsc2-/- cells, but lowered by rapamycin; a pattern referred to as a M-bM-^@M-^\low/low/high/lowM-bM-^@M-^] or M-bM-^@M-^\LLHLM-bM-^@M-^]. We found that mTORC1 regulated the expression of, among other lysosomal genes, V-ATPases through the transcription factor EB (TFEB, Tcfeb in the mouse). The knockdown of Tfeb resulted in the 'flattening' of the LLHL pattern and allowed the identification of genes regulated by mTORC1 through Tfeb Mouse embryo fibroblasts (MEFs) wild type or deficient in Tsc2 expressing a Tfeb shRNA or scrambled shRNA vector were treated with 25 nM rapamycin or vehicle (methanol) for 24 h under low serum conditions (0.1% FBS)
2011-08-02 | E-GEOD-28021 | biostudies-arrayexpress
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
Project description:Mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is a critical regulator of cell growth by integrating multiple signals (nutrients, growth factors, energy and stress) and is frequently deregulated in many types of cancer. We used a robust experimental paradigm involving the combination of two interventions, one genetic and one pharmacologic to identify genes regulated transcriptionally by mTORC1. In Tsc2+/+, but not Tsc2-/- immortalized mouse embryo fibroblasts (MEFs), serum deprivation downregulates mTORC1 activity. In Tsc2-/- cells, abnormal mTORC1 activity can be downregulated by treatment with rapamycin (sirolimus). By contrast, rapamycin has little effect on mTORC1 in Tsc2+/+ cells in which mTORC1 is already inhibited by low serum. Thus, under serum deprived conditions, mTORC1 activity is low in Tsc2+/+ cells (untreated or rapamycin treated), high in Tsc2-/- cells, but lowered by rapamycin; a pattern referred to as a M-^Slow/low/high/lowM-^T or M-^SLLHLM-^T, which allowed the identification of genes regulated by mTORC1 by performing the appropriate comparisons
2011-08-02 | E-GEOD-27982 | biostudies-arrayexpress