The Role of the miR-451-AMPK Signaling Pathway in Regulation of Cell Migration and Proliferation in Glioblastoma

Glioblastoma is the most aggressive type of brain cancer with a median survival time of 1 year. A particular microRNA, miR-451, and its counterpart, AMPK complex are known to play a key role in controlling the balance between rapid proliferation and aggressive invasion in response to metabolic stress in the microenvironment. The present paper develops a hybrid model of glioblastoma that identifies a key mechanism behind the molecular switches between proliferative phase and migratory phase in response to metabolic stress and biophysical interaction between cells. We first focus on the core miR-451-AMPK control system and show how up- or down-regulation of components of these pathways affects cell proliferation and migration. We then examine a hybrid model for the biomechanical interaction between invasive and proliferative cells, in which all cells are modeled individually, and show how biophysical properties of cells and the core miR-451-AMPK control system affect the growth/invasion patterns of glioma spheroids in response to various glucose levels in the microenvironment. The model predicts that cell migration depends not only on glucose availability but also on mechanical constraints between cells. The model predicts various invasion patterns and cell speeds under normal and low glucose conditions. The hybrid model also predicts that introduction of chemoattractants at the resection site may lead to the localization of infiltrating tumor cells back to the periphery of the resected area, which may lead to possible follow-up treatment options such as the subsequent surgeries and optimized elimination of the infiltrating glioma cells.