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Identification of the lymphangioleiomyomatosis cell and its uterine origin

ABSTRACT: Lymphangioleiomyomatosis (LAM) is a metastasizing neoplasm of reproductive age women which causes cystic lung remodeling and progressive respiratory failure. While LAM lesions are known to contain abnormal smooth muscle-like cells which harbor mTOR activating mutations in TSC1 or TSC2, the tissue origins of the mutant “LAM cells” that invade the lung remain unclear. By employing single cell and single nuclear RNA sequencing on explanted LAM lungs, we identified a unique population of cells and associated signature genes and gene networks which were readily distinguished from those of endogenous lung cells. These unique LAMCORE cells shared closest transcriptomic similarity to normal uterus and share transcriptomic features with neural crest, as identified in uterine LAM lesions by single nuclear RNA-seq. Immunofluorescence microscopy demonstrated the expression of LAMCORE cell signature genes within LAM lesions in both lung and uterus. Serum aptamer proteomics and ELISA identified biomarkers consistent with the signature genes expressed and predicted to be secreted by LAMCORE cells. Single cell transcriptomics strongly supports a uterine neural crest origin of LAMCORE cells; providing insights into disease pathogenesis and informing future treatment strategies for LAM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE135851 | GEO | 2020/07/11

REPOSITORIES: GEO

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Transcript profiling of Lymphangioleiomyomatosis (LAM) nodules in Human Patients

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2008-12-30 | E-GEOD-12027 | biostudies-arrayexpress

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2008-12-31 | GSE12027 | GEO

Sorafenib inhibits invasion of multicellular organoids that mimic Lymphangioleiomyomatosis nodules.

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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

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.

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Transcriptomic Differences Associated with TSC2 Gene Expression Loss in Lymphangioleiomyomatosis [mouse cells]

Project description:Pulmonary Lymphangioleiomyomatosis (LAM), a rare lung disease that affects predominantly women, is characterized by proliferation of smooth muscle-like cells in the lungs, destruction of lung tissue, upregulation of VEGF-D, and growth of lymphatic vessels inducing a loss of pulmonary function. TSC2 gene mutations that render TSC2 inactive are a common finding associated with LAM. To better understand the function of the TSC2 gene, we sought to characterize differences in the transcriptome of cells where TSC2 is inactivated. RNA-Seq was used to measure transcript expression differences between TSC2-null mouse embryonic fibroblasts and TSC2-expressed mouse embryonic fibroblasts. The Illumina TruSeq method was used to prepare stranded poly(A)-selected RNA-Seq libraries, and 100bp paired-end reads were generated with an Illumina Hi-Seq 2500 instrument in high output mode. RNA-Seq data was analyzed using kallisto (http://pachterlab.github.io/kallisto/) and R.

2018-05-23 | GSE84477 | GEO

Expression data from LAM-associated fibroblasts and normal human lung fibroblasts co-cultured with TSC2-/- 621-101 cells

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

Resident effector memory Tregs of the uterus regulate trophic functions during mouse early pregnancy

Project description:Regulatory T cells (Tregs) contribute to successful pregnancy by promoting maternal-fetal tolerance. We identified a novel population of CD25-Foxp3+ resident uterine Tregs in non-pregnant mouse uterus. They have phenotypic and migration properties of tissue-resident effector-memory T cells (Trm), thus identifying regulatory Trm (regTrm). Lack of CD25 expression in regTrm is caused by the IL-2-deprived uterine microenvironment. We performed a complete transcriptome analysis by RNA-seq to determined whether uterine regTrm have a unique molecular signature, as has been described for other tissue Tregs. For this, we purified CD25- regTrm from non-pregnant and pregnant uterus at day 6 to 8 of pregnancy, and we compared them to CD4+Foxp3- (CD4conv) T cells from non-pregnant uterus and to CD25+ Tregs from paraaortic uterine draining lymph nodes. We used criteria of (i) a two-fold or greater change in expression and (ii) a p-value <0.05 (cut-off at 5% FDR) to determine differentially expressed genes (DEGs). DEGs were annotated by their functional relevance in pregnancy using ingenuity pathway analysis (IPA) and using the PubMed Query: (Gene main name OR Gene Synonymous 1 OR Gene Synonymous 2 OR …) AND "pregnancy" OR “regulatory T cells” OR "uterus". We found that uterine regTrm have a unique transcriptional profile, impregnated with a uterine signature comprising up-regulation of genes related to the endometrium and to uterine receptivity. Pregnancy triggers regTrm expression of genes involved in trophic functions such as uterine development, extracellular matrix remodeling, hypoxia and vasculogenesis.

2019-05-01 | GSE109895 | GEO

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