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Tuberous Sclerosis Complex cell‐derived EVs have an altered protein cargo capable of regulating their microenvironment and have potential as disease biomarkers

Muireann Ní Bhaoighill Orcid Logo, Juan M. Falcón‐Pérez Orcid Logo, Félix Royo Orcid Logo, Andrew R. Tee Orcid Logo, Jason Webber Orcid Logo, Elaine A. Dunlop Orcid Logo

Journal of Extracellular Vesicles, Volume: 12, Issue: 6

Swansea University Author: Jason Webber Orcid Logo

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DOI (Published version): 10.1002/jev2.12336

Abstract

Hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) is a feature of many solid tumours and is a key pathogenic driver in the inherited condition Tuberous Sclerosis Complex (TSC). Modulation of the tumour microenvironment by extracellular vesicles (EVs) is known to facilitate the de...

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Published in: Journal of Extracellular Vesicles
ISSN: 2001-3078 2001-3078
Published: Wiley 2023
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URI: https://cronfa.swan.ac.uk/Record/cronfa64712
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Modulation of the tumour microenvironment by extracellular vesicles (EVs) is known to facilitate the development of various cancers. The role of EVs in modulating the tumour microenvironment and their impact on the development of TSC tumours, however, remains unclear. This study, therefore, focuses on the poorly defined contribution of EVs to tumour growth in TSC. We characterised EVs secreted from TSC2-deficient and TSC2-expressing cells and identified a distinct protein cargo in TSC2-deficient EVs, containing an enrichment of proteins thought to be involved in tumour-supporting signalling pathways. We show EVs from TSC2-deficient cells promote cell viability, proliferation and growth factor secretion from recipient fibroblasts within the tumour microenvironment. Rapalogs (mTORC1 inhibitors) are the current therapy for TSC tumours. Here, we demonstrate a previously unknown intercellular therapeutic effect of rapamycin in altering EV cargo and reducing capacity to promote cell proliferation in the tumour microenvironment. 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spelling v2 64712 2023-10-11 Tuberous Sclerosis Complex cell‐derived EVs have an altered protein cargo capable of regulating their microenvironment and have potential as disease biomarkers 25d1a26f9b8bb556bd9412080e40351d 0000-0003-4772-3014 Jason Webber Jason Webber true false 2023-10-11 BMS Hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) is a feature of many solid tumours and is a key pathogenic driver in the inherited condition Tuberous Sclerosis Complex (TSC). Modulation of the tumour microenvironment by extracellular vesicles (EVs) is known to facilitate the development of various cancers. The role of EVs in modulating the tumour microenvironment and their impact on the development of TSC tumours, however, remains unclear. This study, therefore, focuses on the poorly defined contribution of EVs to tumour growth in TSC. We characterised EVs secreted from TSC2-deficient and TSC2-expressing cells and identified a distinct protein cargo in TSC2-deficient EVs, containing an enrichment of proteins thought to be involved in tumour-supporting signalling pathways. We show EVs from TSC2-deficient cells promote cell viability, proliferation and growth factor secretion from recipient fibroblasts within the tumour microenvironment. Rapalogs (mTORC1 inhibitors) are the current therapy for TSC tumours. Here, we demonstrate a previously unknown intercellular therapeutic effect of rapamycin in altering EV cargo and reducing capacity to promote cell proliferation in the tumour microenvironment. Furthermore, EV cargo proteins have the potential for clinical applications as TSC biomarkers, and we reveal three EV-associated proteins that are elevated in plasma from TSC patients compared to healthy donor plasma. Journal Article Journal of Extracellular Vesicles 12 6 Wiley 2001-3078 2001-3078 Extracellular vesicles (EVs), fibroblasts, mTORC1, TSC2, tuberous sclerosis complex (TSC), tumour microenvironment 19 6 2023 2023-06-19 10.1002/jev2.12336 http://dx.doi.org/10.1002/jev2.12336 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University Another institution paid the OA fee Tuberous Sclerosis Association (Grant 2018-S02) 2024-02-01T15:49:11.3048952 2023-10-11T12:04:05.7628849 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Muireann Ní Bhaoighill 0000-0003-3373-1064 1 Juan M. Falcón‐Pérez 0000-0003-3133-0670 2 Félix Royo 0000-0001-9769-4165 3 Andrew R. Tee 0000-0002-5577-4631 4 Jason Webber 0000-0003-4772-3014 5 Elaine A. Dunlop 0000-0002-9209-7561 6 64712__29107__681b30e998fa4232bfcf7a1ca10c81c0.pdf 64712.VOR.pdf 2023-11-24T14:42:29.5569770 Output 1995673 application/pdf Version of Record true © 2023 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles. Distributed under the terms of a Creative Commons Attribution 4.0 International License (CC BY 4.0). true eng https://creativecommons.org/licenses/by/4.0/
title Tuberous Sclerosis Complex cell‐derived EVs have an altered protein cargo capable of regulating their microenvironment and have potential as disease biomarkers
spellingShingle Tuberous Sclerosis Complex cell‐derived EVs have an altered protein cargo capable of regulating their microenvironment and have potential as disease biomarkers
Jason Webber
title_short Tuberous Sclerosis Complex cell‐derived EVs have an altered protein cargo capable of regulating their microenvironment and have potential as disease biomarkers
title_full Tuberous Sclerosis Complex cell‐derived EVs have an altered protein cargo capable of regulating their microenvironment and have potential as disease biomarkers
title_fullStr Tuberous Sclerosis Complex cell‐derived EVs have an altered protein cargo capable of regulating their microenvironment and have potential as disease biomarkers
title_full_unstemmed Tuberous Sclerosis Complex cell‐derived EVs have an altered protein cargo capable of regulating their microenvironment and have potential as disease biomarkers
title_sort Tuberous Sclerosis Complex cell‐derived EVs have an altered protein cargo capable of regulating their microenvironment and have potential as disease biomarkers
author_id_str_mv 25d1a26f9b8bb556bd9412080e40351d
author_id_fullname_str_mv 25d1a26f9b8bb556bd9412080e40351d_***_Jason Webber
author Jason Webber
author2 Muireann Ní Bhaoighill
Juan M. Falcón‐Pérez
Félix Royo
Andrew R. Tee
Jason Webber
Elaine A. Dunlop
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container_title Journal of Extracellular Vesicles
container_volume 12
container_issue 6
publishDate 2023
institution Swansea University
issn 2001-3078
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doi_str_mv 10.1002/jev2.12336
publisher Wiley
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
url http://dx.doi.org/10.1002/jev2.12336
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description Hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) is a feature of many solid tumours and is a key pathogenic driver in the inherited condition Tuberous Sclerosis Complex (TSC). Modulation of the tumour microenvironment by extracellular vesicles (EVs) is known to facilitate the development of various cancers. The role of EVs in modulating the tumour microenvironment and their impact on the development of TSC tumours, however, remains unclear. This study, therefore, focuses on the poorly defined contribution of EVs to tumour growth in TSC. We characterised EVs secreted from TSC2-deficient and TSC2-expressing cells and identified a distinct protein cargo in TSC2-deficient EVs, containing an enrichment of proteins thought to be involved in tumour-supporting signalling pathways. We show EVs from TSC2-deficient cells promote cell viability, proliferation and growth factor secretion from recipient fibroblasts within the tumour microenvironment. Rapalogs (mTORC1 inhibitors) are the current therapy for TSC tumours. Here, we demonstrate a previously unknown intercellular therapeutic effect of rapamycin in altering EV cargo and reducing capacity to promote cell proliferation in the tumour microenvironment. Furthermore, EV cargo proteins have the potential for clinical applications as TSC biomarkers, and we reveal three EV-associated proteins that are elevated in plasma from TSC patients compared to healthy donor plasma.
published_date 2023-06-19T15:49:11Z
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