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journal article·2023-09Open access

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

Adam Pietrobon, Julien Yockell‐Lelièvre, Nicole Melong, Laura J. Smith, Sean P. Delaney, Nadine Azzam, Chang Xue, Nishanth Merwin, Eric Lian, Alberto Camacho‐Magallanes, Carole Doré, Gabriel Musso, Lisa M. Julian, Arnold S. Kristof, Roger Y. Tam, Jason N. Berman, Molly S. Shoichet, William L. Stanford

Advanced Science· Volume 10· Issue 26
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Source abstract

Abstract

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.
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Research context

PolymersBiomaterials

OpenAlex topics: Tuberous Sclerosis Complex Research · Epigenetics and DNA Methylation · Renal and related cancers

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

The Sprott Centre for Stem Cell Research Regenerative Medicine Program Ottawa Hospital Research Institute Ottawa K1Y 4E9 Canada

Department of Cellular and Molecular Medicine University of Ottawa Ottawa K1N 6N5 Canada

Ottawa Institute of Systems Biology Ottawa K1H 8M5 Canada

Department of Pediatrics CHEO Research Institute Ottawa K1H 5B2 Canada

Department of Chemical Engineering and Applied Chemistry University of Toronto Toronto M5S 3E5 Canada

Institute for Biomaterials and Biomedical Engineering University of Toronto Toronto M5S 3G9 Canada

The Donnelly Centre for Cellular and Biomolecular Research Toronto M5S 3E1 Canada

BioSymetrics Inc. Toronto M5T 1X5 Canada

Centre for Cell Biology Development and Disease Department of Biological Sciences Simon Fraser University Burnaby V5A 1S6 Canada

Meakins‐Christie Laboratories and Translational Research in Respiratory Diseases Program Research Institute of the McGill University Health Centre Faculty of Medicine Departments of Medicine and Critical Care Montreal H4A 3J1 Canada

Centre for Biologics Evaluation Biologic and Radiopharmaceutical Drugs Directorate Health Canada Ottawa K1Y 4X2 Canada

Department of Chemistry University of Toronto Toronto M5S 3H6 Canada

Funding

Ontario Institute for Cancer Research · Canada Research Chairs · LAM Foundation

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