Breast cancer brain metastases (BCBM) affect nearly 90,000 patients with breast cancer in the United States annually and carry a significant risk of mortality. As metastatic lesions develop, the unique milieu of the brain microenvironment shapes disease progression and therapeutic response, but the contribution of astrocytes to metastasis formation and treatment response is not well understood. 

Using a computational model for tumor growth, we simulated BCBM formation and astrocyte behavior on a 2D lattice. In our model, tumor cells convert astrocytes from anti- to pro-metastatic, which in turn increases the division rate of tumor cells. We simulated chemotherapy and radiotherapy treatment to examine tumor growth dynamics across different astrocyte distributions, conversion rates, and dosing schedules. 

Our results showed that the reprogramming of astrocytes led to an increased tumor growth rate and recapitulates chemoresistance. As a result, our model predicts greater anti-tumor effects from radiotherapy due to its deleterious effects on both tumor cells and astrocytes, with the gain in efficacy varying based on underlying astrocyte density. This suggests a potential differential effect of radiotherapy in regions of brain with varying astrocyte densities. Our model suggests that inhibiting conversion of astrocytes from anti- to pro-metastatic, when combined with radiotherapy and chemotherapy, enhances tumor control, especially in regions of high astrocyte density. 

Our findings highlight that astrocyte reprogramming promotes tumor growth and recapitulates chemoresistance, suggesting that tailoring radiotherapy to underlying astrocyte density and targeting astrocyte conversion with specific inhibitors could enhance treatment outcomes in breast cancer brain metastases.