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 can...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-09-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202302611 |
| _version_ | 1797684956272525312 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Adam Pietrobon |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T00:37:22Z |
| format | Article |
| id | doaj.art-a106fabeaeb643adbc219e24ad198f59 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-03-12T00:37:22Z |
| publishDate | 2023-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-a106fabeaeb643adbc219e24ad198f592023-09-15T09:28:59ZengWileyAdvanced Science2198-38442023-09-011026n/an/a10.1002/advs.202302611Tissue‐Engineered Disease Modeling of Lymphangioleiomyomatosis Exposes a Therapeutic Vulnerability to HDAC InhibitionAdam Pietrobon0Julien Yockell‐Lelièvre1Nicole Melong2Laura J. Smith3Sean P. Delaney4Nadine Azzam5Chang Xue6Nishanth Merwin7Eric Lian8Alberto Camacho‐Magallanes9Carole Doré10Gabriel Musso11Lisa M. Julian12Arnold S. Kristof13Roger Y. Tam14Jason N. Berman15Molly S. Shoichet16William L. Stanford17The Sprott Centre for Stem Cell Research Regenerative Medicine Program Ottawa Hospital Research Institute Ottawa K1Y 4E9 CanadaThe Sprott Centre for Stem Cell Research Regenerative Medicine Program Ottawa Hospital Research Institute Ottawa K1Y 4E9 CanadaDepartment of Pediatrics CHEO Research Institute Ottawa K1H 5B2 CanadaDepartment of Chemical Engineering and Applied Chemistry University of Toronto Toronto M5S 3E5 CanadaThe Sprott Centre for Stem Cell Research Regenerative Medicine Program Ottawa Hospital Research Institute Ottawa K1Y 4E9 CanadaDepartment of Pediatrics CHEO Research Institute Ottawa K1H 5B2 CanadaInstitute for Biomaterials and Biomedical Engineering University of Toronto Toronto M5S 3G9 CanadaBioSymetrics Inc. Toronto M5T 1X5 CanadaThe Sprott Centre for Stem Cell Research Regenerative Medicine Program Ottawa Hospital Research Institute Ottawa K1Y 4E9 CanadaThe Sprott Centre for Stem Cell Research Regenerative Medicine Program Ottawa Hospital Research Institute Ottawa K1Y 4E9 CanadaThe Sprott Centre for Stem Cell Research Regenerative Medicine Program Ottawa Hospital Research Institute Ottawa K1Y 4E9 CanadaBioSymetrics Inc. Toronto M5T 1X5 CanadaCentre for Cell Biology Development and Disease Department of Biological Sciences Simon Fraser University Burnaby V5A 1S6 CanadaMeakins‐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 CanadaCentre for Biologics Evaluation Biologic and Radiopharmaceutical Drugs Directorate Health Canada Ottawa K1Y 4X2 CanadaDepartment of Cellular and Molecular Medicine University of Ottawa Ottawa K1N 6N5 CanadaDepartment of Chemical Engineering and Applied Chemistry University of Toronto Toronto M5S 3E5 CanadaThe Sprott Centre for Stem Cell Research Regenerative Medicine Program Ottawa Hospital Research Institute Ottawa K1Y 4E9 CanadaAbstract 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.https://doi.org/10.1002/advs.2023026113D drug screenbiomimetic hydrogel cultureHDAC inhibitionlymphangioleiomyomatosismTORC1therapeutics development |
| spellingShingle | 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 Tissue‐Engineered Disease Modeling of Lymphangioleiomyomatosis Exposes a Therapeutic Vulnerability to HDAC Inhibition Advanced Science 3D drug screen biomimetic hydrogel culture HDAC inhibition lymphangioleiomyomatosis mTORC1 therapeutics development |
| title | Tissue‐Engineered Disease Modeling of Lymphangioleiomyomatosis Exposes a Therapeutic Vulnerability to HDAC Inhibition |
| title_full | Tissue‐Engineered Disease Modeling of Lymphangioleiomyomatosis Exposes a Therapeutic Vulnerability to HDAC Inhibition |
| title_fullStr | Tissue‐Engineered Disease Modeling of Lymphangioleiomyomatosis Exposes a Therapeutic Vulnerability to HDAC Inhibition |
| title_full_unstemmed | Tissue‐Engineered Disease Modeling of Lymphangioleiomyomatosis Exposes a Therapeutic Vulnerability to HDAC Inhibition |
| title_short | Tissue‐Engineered Disease Modeling of Lymphangioleiomyomatosis Exposes a Therapeutic Vulnerability to HDAC Inhibition |
| title_sort | tissue engineered disease modeling of lymphangioleiomyomatosis exposes a therapeutic vulnerability to hdac inhibition |
| topic | 3D drug screen biomimetic hydrogel culture HDAC inhibition lymphangioleiomyomatosis mTORC1 therapeutics development |
| url | https://doi.org/10.1002/advs.202302611 |
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