Page 194 - Molecular features of low-grade developmental brain tumours

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CHAPTER 8
together LAMTOR1-5 can form a complex, known as the “Ragulator” complex, which is known to activate both mTORC1 and MAPK/ERK pathways. Providing initial evidence of a possible link between the constitutive activated mTORC1 pathway and the MAPK/ERK pathway in SEGA.
In chapter 5, the role of the extracellular matrix in SEGAs was studied in more detail. Matrix metalloproteinases (MMPs), together with their tissue inhibitors (TIMPs) are responsible for the remodeling of the extracellular matrix and are known to be involved in processes associated with tumourgenesis, such as proliferation, cell migration and angiogenesis. We identified a dysregulation of the MMP/TIMP proteolytic system in SEGAs. Additionally, we identified the lowly expressed microRNA (miRNA), miR-320d in SEGA compared to control as a potential regulator of MMP2, MMP11, MMP14, MMP15, MMP19, which can decrease MMP2 expression in human fetal astrocyte cultures. This suggests targeting MMPs potentially with miR-320d alone or in combination with other MMP targeting miRNAs, could be of interest as a therapeutic intervention for TSC patients with SEGA.
In chapter 6, we found miR-519d and miR-4758 to be upregulated in GGs compared to control tissue, DNTs and other astrocytomas, including SEGAs, suggesting that these miRNAs could be considered as additional markers in the classification of LEATs. The PI3K/AKT3/P21 pathway, a pathway commonly deregulated in cancer, was also deregulated in GGs. Functionally, overexpression of miR-519d in an astrocytic cell line resulted in a downregulation of CDKN1A (P21) and an increase in cell proliferation, whereas co-transfection with miR-4758 counteracted this effect, suggesting that these miRNAs might work in concert as regulators of the cell cycle in low grade gliomas.
The findings of these studies are discussed in chapter 7. Overall, this thesis shows that the MAPK/ERK pathway is activated in SEGAs, suggesting that this pathway could be used as a target for treatment independent of, or in combination with mTOR inhibitors for TSC patients with SEGAs. This activation cannot be explained by the BRAFV600E mutation, which is a common genetic driver in GGs and other low-grade GNTs. Alternatively, the overexpression of LAMTOR1-5 in SEGAs provides a new link between the MAPK and mTOR pathway in SEGAs and could therefore also play an interesting role in other tumours where both pathways are effected. Furthermore, we show how miRNAs can be used to distinguish between tumour entities and how they can target important pathways in both SEGAs and GNTs.