A175
Role of the metabolic autophagy pathway in glioma
Background
High-grade gliomas (HGG) remain among the poorest prognosis primary tumours of adults. One of the factors underlying such dismal prognosis is the ability of glioma cells to invade the brain parenchyma, which makes surgical debulking almost invariably insufficient. Glioma is highly heterogeneous and can be classified into molecular subclasses. Among them, the mesenchymal subtype is characterised by mesenchymal/angiogenic markers and is associated with poor survival. The metabolic autophagy pathway has been proposed to contribute to disease progression in aggressive cancers. However, its precise role in glioma has not been fully elucidated.
Method
We analysed autophagy status in glioma by using publicly available gene expression datasets from over 400 patient samples. Next, we studied autophagy in glioma-initiating cells and determined the impact of its suppression on growth, migration/invasion and bioenergetics. Finally, we investigated the involvement of RAS/MAPK as an upstream regulator of autophagy.
Results
We found that a number of autophagy genes, such as DRAM1 and SQSTM1/p62 are highly expressed in glioma tumours belonging to the mesenchymal subclass. High expression of the autophagy inducer DRAM1 correlates with shorter overall survival in glioma patients. Autophagy appears to be under the control of the RAS/MAPK pathway in glioma. In glioma-initiating cells, suppression of autophagy impairs ATP production migration/invasion without overt effects on survival. reduction in ATP levels and dramatic changes in mitochondria morphology. Finally, autophagy inhibition affects mesenchymal cell migration in cancer epithelial cells undergoing epithelial-to-mesenchymal transition (EMT).
Conclusion
Taken together, these findings shed new light on the role of autophagy in the tumour-initiating cell fraction of HGG and implicate this metabolic pathway in the control of cancer cell migration.