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Updated: Apr 18, 2026
Translational Orthotopic Models of Glioblastoma Multiforme
Published on: February 17, 2023
Strategies of eradicating glioma cells: a multi-scale mathematical model with MiR-451-AMPK-mTOR control
Yangjin Kim1, Gibin Powathil2, Hyunji Kang3
1Department of Mathematics, Konkuk University, Seoul, 143-701, Republic of Korea; Department of Mathematics, Ohio State University, Columbus, OH 43210, USA.
Abstract:
The cellular dispersion and therapeutic control of glioblastoma, the most aggressive type of primary brain cancer, depends critically on the migration patterns after surgery and intracellular responses of the individual cancer cells in response to external biochemical and biomechanical cues in the microenvironment. Recent studies have shown that a particular microRNA, miR-451, regulates downstream molecules including AMPK and mTOR to determine the balance between rapid proliferation and invasion in response to metabolic stress in the harsh tumor microenvironment. Surgical removal of main tumor is inevitably followed by recurrence of the tumor due to inaccessibility of dispersed tumor cells in normal brain tissue. In order to address this multi-scale nature of glioblastoma proliferation and invasion and its response to conventional treatment, we propose a hybrid model of glioblastoma that analyses spatio-temporal dynamics at the cellular level, linking individual tumor cells with the macroscopic behaviour of cell organization and the microenvironment, and with the intracellular dynamics of miR-451-AMPK-mTOR signaling within a tumour cell. The model identifies a key mechanism underlying the molecular switches between proliferative phase and migratory phase in response to metabolic stress and biophysical interaction between cells in response to fluctuating glucose levels in the presence of blood vessels (BVs). The model predicts that cell migration, therefore efficacy of the treatment, not only depends on oxygen and glucose availability but also on the relative balance between random motility and strength of chemoattractants. Effective control of growing cells near BV sites in addition to relocalization of invisible migratory cells back to the resection site was suggested as a way of eradicating these migratory cells.
Insights
This study models glioblastoma, linking cellular migration and intracellular signaling (miR-451-AMPK-mTOR) to predict treatment efficacy. It suggests controlling invasive cells near blood vessels and relocating migratory cells improves glioblastoma eradication.
Area of Science:
- Computational Biology
- Cancer Research
- Systems Biology
Background:
- Glioblastoma dispersion and recurrence post-surgery are driven by cellular migration and intracellular responses to microenvironmental cues.
- MicroRNA miR-451 regulates proliferation-invasion balance via AMPK and mTOR pathways under metabolic stress.
- Tumor recurrence highlights the challenge of dispersed cells and the need for multi-scale modeling.
Purpose of the Study:
- To develop a hybrid model analyzing glioblastoma's spatio-temporal dynamics at cellular and intracellular levels.
- To link individual cell behavior, macroscopic organization, microenvironment, and miR-451-AMPK-mTOR signaling.
- To understand molecular switches between proliferation and migration in response to metabolic and biophysical cues.
Main Methods:
- Developed a hybrid computational model integrating cellular dynamics, microenvironment interactions, and intracellular signaling pathways.
- Simulated spatio-temporal dynamics of glioblastoma cells under varying metabolic conditions (glucose, oxygen).
- Analyzed the influence of cell motility, chemoattractants, and blood vessel proximity on tumor behavior.
Main Results:
- Identified a key mechanism controlling the switch between proliferative and migratory phases based on metabolic stress and cell-cell interactions.
- Demonstrated that cell migration and treatment efficacy depend on nutrient availability and the balance between random motility and chemoattraction.
- Highlighted the critical role of glucose fluctuations near blood vessels in regulating cell behavior.
Conclusions:
- Effective glioblastoma control requires managing cells near blood vessels and relocating invasive cells to the resection site.
- The model provides insights into glioblastoma's multi-scale complexity and response to therapy.
- Targeting miR-451-AMPK-mTOR signaling and understanding migration dynamics are crucial for improving treatment outcomes.
