A new study has found that extracellular vesicles (EVs)—tiny, cell-derived particles circulating in the bloodstream—may serve as effective biomarkers for diagnosing and monitoring tuberous sclerosis complex (TSC). The research shows that specific proteins carried by EVs can reliably distinguish individuals with TSC from healthy donors, offering a potential breakthrough in clinical detection and disease tracking.
Researchers reported that three EV-associated proteins—endoglin, enolase γ, and VEGF—were significantly elevated in plasma samples from people with TSC. When combined into a single score, these markers effectively differentiated TSC patients from controls, highlighting their potential for future diagnostic use.
While mTORC1 inhibitors, such as rapamycin and everolimus, are a standard treatment for TSC-associated tumors like renal angiomyolipoma and subependymal giant cell astrocytomas(SEGAs), their efficacy can vary from person to person. In cancer, tumor-derived EVs are known to influence tumor development by modifying the tumor microenvironment. This study aimed to understand the role of EVs in TSC tumor growth and their potential as clinical biomarkers. The researchers utilized blood samples from the TSC Alliance Biosample Repository and Cardiff University.
Distinct EV Protein Cargo in TSC
The research found that EVs secreted from TSC2-deficient cells (cells with over-active mTORC1, as in TSC) have a distinct protein cargo compared to EVs from TSC2-expressing cells. This cargo includes an enrichment of proteins associated with tumor-supporting signaling pathways. Specifically, 29 tumor-associated proteins showed altered expression in EVs from TSC2-deficient cells. Proteins including IL-6, MMPs, VEGF, and Galectin-3, previously linked to mTORC1-driven tumors, were found to be elevated in TSC2-deficient EVs. Functional enrichment analysis revealed that these upregulated proteins are involved in pathways such as cell-to-cell interactions and mTOR signaling, suggesting their role in disease progression.
Impact of Rapamycin Treatment on EVs
Rapamycin treatment was shown to alter the protein cargo of EVs from TSC2-deficient cells. It significantly reduced the levels of EV-associated endoglin, enolase γ, IL-6, and CCL20, making them more similar to levels observed in EVs from non-TSC2-deficient cells. This suggests that some of the therapeutic effect of mTORC1 inhibitors may be by altering EV cargo and reducing their capacity to promote cell proliferation in the tumor microenvironment. However, rapamycin treatment did not reduce the protein abundance of VEGF in TSC2-deficient EVs and, in some cases, VEGF cargo even increased. This indicates that some features of TSC2-deficient EVs are not fully attenuated by rapamycin, possibly due to mTOR-independent pathways.
EVs as Potential Biomarkers for TSC
The study found that endoglin, enolase γ, and VEGF were significantly elevated in EVs from plasma of individuals with TSC compared to healthy donors. When these protein levels were combined and scored, they effectively differentiated between people with and without TSC. This highlights the potential of EV-associated proteins as novel and accessible biomarkers for diagnosing and monitoring TSC. Further development is needed, but these findings offer promising avenues for clinical application.
Lead author: Elaine A. Dunlop, PhD, Senior Lecturer, Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom.
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