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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE179044 | GEO | 2023/07/06

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.

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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]

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Estrogen and mTORC1 dependent genes in the uterus of uterine-specific Tsc2-null mice

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 17Î²-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

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

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Estrogen and mTORC1 dependent genes in the uterus of uterine-specific Tsc2-null mice

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

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2011-08-02 | E-GEOD-27982 | biostudies-arrayexpress

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