Drug Resistance Effect on Metastasis by Activating EMT Pathway in Meningioma

2023-1-16
Karakaya, İdil Gül
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Cancer is one of the leading and often fatal diseases in humans. Cancerous cells can arise within any tissue or organ in the body. Treatment of cancer includes but is not limited to radiotherapy, chemotherapy, immunotherapy, or targeted therapy options. Meningioma, one of the brain malignancies, is the subject of this research. As it is known, cancer cells can spread to other organs and this is called metastasis. Different biological pathways contribute to the migration of cells. Epithelial to mesenchymal transition (EMT) is the pathway that primarily affects cancer metastasis. Certain EMT indicators and transcription factors are differentially regulated as the EMT pathway is activated. E-cadherin, N-cadherin, Vimentin, and β–Catenin are important EMT indicators. In our study, CDH1 expression is lower in a benign meningioma cell line, AC599, compared to a malignant meningioma cell line, IOMM Lee. It is well known that CDH2 and VIM expressions increase, while CDH1 expressions decrease during EMT. This increment of VIM and CDH2 has been seen in the AC599 meningioma cell line upon gaining JQ1 drug resistance (AC599 JR). We observed that the expression of SNAIL, SLUG, and TWIST is increased in the vi JQ1 Resistant AC599 cell line (AC599 JR) more than in the JQ1 Resistant IOMM Lee (IOMM Lee JR) cell line. Chemoresistance is a major obstacle in cancer therapy and could be caused by various factors and pathways, among which the EMT mechanism has recently received attention for its role in drug resistance in addition to metastasis. EMT contributes to drug resistance in many cancer types, especially pancreatic, bladder, and breast cancer. Overall, our study indicates that JQ1 drug resistance increases migration and mesenchymal properties of AC599, benign meningioma cell line more than IOMM Lee, malignant meningioma cell line. RNAseq data indicates that STAT family transcription factors play a major role in JQ1 chemoresistant meningioma cell lines. STAT3 inhibition by using Stattic reduces meningioma cell proliferation and migration, and in some cases stops cell migration. This observation is specific to the NF2 mutation status of meningioma. NF2 protein is known to play a role in EMT activation and NF2 loss is very common in meningioma which is associated with the downregulation of CDH1 in meningioma. In conclusion, JQ1 and Stattic drug treatments are viable therapy options for meningioma chemotherapy. Furthermore, our results suggest the importance of cell and pathway-specific approaches for effective cancer treatment.
JQ1, Meningioma, EMT pathway, Drug resistance, Bromodomain inhibitor
https://hdl.handle.net/11511/102111
Graduate School of Natural and Applied Sciences, Thesis

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Citation Formats
İ. G. Karakaya, “Drug Resistance Effect on Metastasis by Activating EMT Pathway in Meningioma,” M.S. - Master of Science, Middle East Technical University, 2023.
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