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

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

PROVIDER: PRJNA742011 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14930729_1.fastq.gz	Fastqsanger.gz
	SRR14930729_2.fastq.gz	Fastqsanger.gz
	SRR14930730_1.fastq.gz	Fastqsanger.gz
	SRR14930730_2.fastq.gz	Fastqsanger.gz
	SRR14930731_1.fastq.gz	Fastqsanger.gz

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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

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.

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Identification of Asporin as a HER3 ligand that exposes a therapeutic vulnerability in metastatic prostate cancer

Project description:Identification of Asporin as a HER3 ligand that exposes a therapeutic vulnerability in metastatic prostate cancer

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Identification of Asporin as a HER3 ligand that exposes a therapeutic vulnerability in metastatic prostate cancer (ASPN)

Project description:Identification of Asporin as a HER3 ligand that exposes a therapeutic vulnerability in metastatic prostate cancer (ASPN)

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Identification of Asporin as a HER3 ligand that exposes a therapeutic vulnerability in metastatic prostate cancer (NRG1)

Project description:Identification of Asporin as a HER3 ligand that exposes a therapeutic vulnerability in metastatic prostate cancer (NRG1)

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Identification of Asporin as a HER3 ligand that exposes a therapeutic vulnerability in metastatic prostate cancer [ASPN_MyCCaP_10111-AH]

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Identification of Asporin as a HER3 ligand that exposes a therapeutic vulnerability in metastatic prostate cancer [NRG1_MyCCaP_10722-AH]

Project description:Identification of Asporin as a HER3 ligand that exposes a therapeutic vulnerability in metastatic prostate cancer [NRG1_MyCCaP_10722-AH]

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Identification of Asporin as a HER3 ligand that exposes a therapeutic vulnerability in metastatic prostate cancer [LNCaP_EnzaResistant_9445-HYW]

Project description:Identification of Asporin as a HER3 ligand that exposes a therapeutic vulnerability in metastatic prostate cancer [LNCaP_EnzaResistant_9445-HYW]

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Identification of Asporin as a HER3 ligand that exposes a therapeutic vulnerability in metastatic prostate cancer [VCaP_EnzaResistant_9817-HYW]

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An epigenetic vulnerability in PI3K/AKT inhibition resistant cancers is targetable by both bromodomain and HDAC inhibitors

Project description:Acquisition of resistance to PI3K/AKT-targeted monotherapy regardless of cancer types implies the existence of common mechanisms. Here we demonstrate that while causing glycolysis crisis, acetyl-CoA shortage and global decrease of histone acetylation, PI3K/AKT inhibitors induce drug resistance by selectively augmenting CBP/p300, H3K27 acetylation and BRD4 binding at genomic loci of a subset of growth factor and receptor (GF/R) genes. BRD4 occupation at these loci and drug resistant cell growth are vulnerable to both bromodomain and HDAC inhibitors. Little or none occupation of HDACs at the GF/R gene loci underscores the paradox that cells respond equivalently to the two classes of inhibitors with opposite modes of action. Targeting this unique epigenetic vulnerability offers a general solution to overcome PI3K/AKT inhibitor resistance in different cancers.

2020-09-09 | GSE147455 | GEO

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