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Characterising the role of extracellular vesicles in tuberous sclerosis complex

Ni Bhaoighill, Muireann 2022. Characterising the role of extracellular vesicles in tuberous sclerosis complex. PhD Thesis, Cardiff University.
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Abstract

Tuberous Sclerosis Complex (TSC) is a rare autosomal-dominant genetic disease, caused by loss-of-function mutations in TSC1 or TSC2 tumour suppressor genes. TSC1/TSC2 mutations cause hyperactivation of mammalian Target Of Rapamycin Complex 1 (mTORC1), a master regulator of cell growth and survival, causing development of hamartomas (benign growths) in vital organs, including the kidneys, brain, heart, and lungs. While intracellular signalling is well elucidated in TSC, little is currently known about how TSC tumour cells signal intercellularly to propagate optimal tumour growth and survival. A key mechanism of intercellular signalling is the secretion of small extracellular vesicles (sEVs) that transfer bioactive material from their parental cells to recipient cells in the tumour microenvironment and at distant sites. Thus, the aim of this research was to characterise the role of sEVs in TSC tumour biology. Additionally, sEVs from TSC patient plasma were examined for candidate biomarkers. This research showed that TSC kidney tumour angiomyolipoma (AML) cells secrete sEVs with classical biophysical and molecular characteristics. These AML sEVs were found to have a distinct RNA cargo, enriched in networks associated with various tumour-supporting processes, including extracellular matrix remodeling, growth factor and receptor binding, and angiogenesis. AML sEVs also had a distinct protein cargo (compared to control sEVs) with potential to promote pro-tumoral signalling. Standard-of-care mTORC1 inhibitor rapamycin treatment did not alter characteristics of secreted sEVs, but sEVs from rapamycin-treated AML cells had altered protein cargo and subsequent reduced signalling activation capacity compared to sEVs from untreated AML cells. Lastly, three proteins were found to have elevated expression in TSC patient plasma sEVs compared to healthy donor control sEVs, suggesting their potential as the first biofluid-based biomarkers for TSC. This study reveals important new knowledge about the contribution of sEVs to TSC tumour growth, and their potential application as disease biomarkers.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 17 March 2023
Last Modified: 16 Mar 2024 02:30
URI: https://orca.cardiff.ac.uk/id/eprint/157777

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