Brain microenviornment-dependent lineage plasticity drives adaptation to targeted therapy in malignant gliomas - PROJECT SUMMARY/ABSTRACT Malignant gliomas are the most common primary adult brain cancer, affecting over 20,000 Americans each year. While molecularly targeted therapies have demonstrated tremendous successes in other malignancies, there is a lack of effective and personalized therapeutic approaches for these deadly brain cancers. The goal of this study is to investigate the complex phenomena of phenotypic plasticity in glioblastoma (GBM), the most lethal of all brain tumors in adults, in driving resistance to targeted therapies via non-genetic mechanisms facilitated by the unique brain microenvironment. Extensive preliminary data, which incorporate a large cohort of genetically diverse preclinical glioma models and drugs in clinical development for GBM, indicate the oncogene epidermal growth factor receptor (EGFR) maintains a radial glia (RG)-like cell state in GBM, which drives glioma initiation, heterogeneity, and plasticity. Moreover, preliminary data demonstrate pharmacologic ablation of EGFR induces lineage reprogramming from RG-like to neural/oligodendrocyte progenitor (NPC/OPC)-like programs uniquely in the brain microenvironment, which is hypothesized to drive rapid adaptation and resistance to EGFR-targeted therapy. Specific Aim 1 utilizes cutting-edge single-cell RNA sequencing (scRNA-seq) combined with an innovative genetic fluorescent reporter system and high-resolution barcoded lineage tracing to elucidate the evolutionary mechanisms driving lineage transformations following targeted therapy in GBM. Through the use of state-of-the-art preclinical models that capture the unique brain microenvironment, this approach is expected to provide unprecedented insights into the influence of the brain environment in driving cellular dynamics and lineage transformations during response to therapeutic interventions. Specific Aim 2 focuses on defining the signaling pathways that facilitate brain microenvironment-dependent lineage transitions that drive resistance to oncogene ablation in GBM. Using novel, clinical stage molecularly targeted therapeutics and innovative in vitro models of the brain microenvironment, this aim will uncover the pivotal signaling pathways and brain-derived factors that drive lineage transitions and contribute to resistance against EGFR-targeted therapies in malignant gliomas. Overall, this project represents a significant step towards a deeper understanding of the molecular and cellular mechanisms underpinning tumor heterogeneity and therapy resistance in GBM. By elucidating the dynamics of cellular state transitions and the role of the brain microenvironment in these processes, this work has the potential to significantly impact the development of more effective, targeted treatment strategies for patients suffering from this devastating disease.
