Astrocyte Reprogramming Drives Tumor Progression and Chemotherapy Resistance in Agent-Based Models of Breast Cancer Brain Metastases

by Rupleen Kaur, Rowan Barker-Clarke, and Andrew Dhawan.

Patients with advanced cancer frequently develop brain metastases, resulting in poor survival rates and limited therapeutic options. Understanding the interactions between tumor cells and the brain microenvironment remains challenging. This project employs an agent-based model to demonstrate how brain-resident astrocytes, when reprogrammed by tumor cells, can enhance tumor growth and facilitate drug resistance. By simulating distinct brain regions and quantifying tumor morphology and treatment responses, the study shows how the local microenvironment influences tumor expansion and therapeutic outcomes.

Tumor cells reprogram brain-resident astrocytes from an anti-metastatic to a pro-metastatic phenotype. Agent-based modeling reveals that astrocyte density and distribution across distinct brain regions (A-C) determine tumor expansion and morphological complexity. High uniform density (B) increases lacunarity but decreases eccentricity, producing irregular yet circular tumors. Gradient distribution (C) drives directional expansion with high eccentricity and fractal complexity but reduced lacunarity. These microenvironment-dependent morphological phenotypes may influence tumor progression and treatment outcomes.