Plugging the brain drain: exploring brain tumor dynamics and effective treatments

Abstract

Brain malignancies can be classified into two categories: primary tumors that originate within the brain tissue, such as gliomas, and secondary tumors known as metastases, which originate elsewhere in the body and subsequently spread to the brain. Among brain metastases (BrM), the most common primary tumors associated with their development are lung, melanoma, and breast cancers (BCs). Despite advancements in tumor detection, local treatments, and the emergence of novel therapies, the prognosis for individuals diagnosed with aggressive brain cancer remains discouraging. The 5-year overall survival rates are unfortunately low, underlining the critical need for a deeper understanding of this disease to help with the development of effective treatment strategies. Chapter 1, I introduce all concepts that are important for this thesis. Chapter 2 focuses on the use of mouse BCBM models developed in our laboratory to study the mechanism of chemoresistance. We demonstrate how tumor cells can overexpress the breast cancer resistance protein (BCRP) to adapt to new environments, ultimately leading to therapy resistance. This research sheds light on the underlying mechanisms of chemoresistance and provides important insights into potential strategies for overcoming this challenge. Chapter 3 introduces a novel combination of treatments for the effective management of brain metastases, with a specific focus on immune checkpoint inhibition. We propose a unique strategy to modulate the brain microenvironment by employing doxorubicin treatments, which induce tumor senescence. This induction triggers the recruitment of cytotoxic T cells expressing PD1. Subsequently, immune checkpoint blockade is applied, leading to a remarkable increase in the survival rate of mice. These findings offer insights into the potential implementation of immune checkpoint inhibitors specifically for brain metastases and provide valuable information for the development of improved therapeutic strategies. In Chapters 4 and 5, I will focus on a significant issue associated with brain tumors: their invasive potential. In Chapter 4, I highlight the significance of GFAP-isoforms in regulating glioma invasion and tumor dynamics by employing intravital microscopy. I emphasize the importance of understanding the invasive behaviors of various GFAP-positive populations within glioma tumors, as it can greatly contribute to the development of more effective therapies against invasion. Moving on to Chapter 5, the focus shifts to investigating the behavior of brain metastases in the absence of treatment using intravital microscopy. Our findings reveal that the process known as epithelial-to-mesenchymal transition (EMT) plays a pivotal role in driving the local invasion of brain metastases. By targeting the migration of these mesenchymal tumor cells through the knockdown of ARPC3, we observe a significant decrease in the probability of tumor recurrence in mice. We also discover that these mesenchymal tumor cells exhibit plasticity and possess the ability to form new metastatic lesions when reinjected into the brains of mice. To validate the relevance of our findings in a clinical context, we analyze a small cohort of resected human breast cancer brain metastases. Overall, these chapters offer a comprehensive exploration of various aspects related to glioma invasion, brain metastasis, and chemoresistance. Through the use of advanced imaging techniques, preclinical models, and clinical validation, we contribute to our understanding of the underlying mechanisms and potential therapeutic avenues for brain tumors.