Targeting Glioblastoma Stem Cells - PROJECT SUMMARY/ABSTRACT Glioblastoma represents one of the most lethal types of cancers. Despite extensive molecular characterization, precision medicine efforts have largely failed for glioblastoma therapy, suggesting that these complex tumors are resilient ecosystems that overcome singular therapeutic approaches. Aging is strongly associated with increased incidence and mortality of most cancers, including glioblastoma. However, the cellular and molecular mechanisms by which aging promotes tumor initiation and progression remain poorly understood. Tissue-specific stem cells contribute to development, renewal, and regeneration of most organs. Neural stem cells (NSCs) undergo little to no cell division during normal homeostasis but become activated by tissue injury with wound responses. NSCs reside in specialized niches that provide maintenance cues and regulate the balance between quiescence and proliferation. Inflammation and nutrient constraints in NSC niches in the aging brain promotes quiescence and decreased regenerative potential. Like the normal brain, glioblastomas contain cellular hierarchies with stem-like tumor cells at the apex. While controversial, these cancer stem cells contribute to therapeutic resistance, invasion into normal brain, generation of new vasculature, and evasion of anti-tumor immunity. Cancer stem cells display remarkable plasticity, rendering therapeutic targeting strategies challenging. In the proposed studies, the Rich laboratory will leverage insights from aging in the nervous system and the molecular circuitry of cancer stem cells to understand how aging promotes tumor growth through cell autonomous mechanisms and interactions with the microenvironment. We will leverage preliminary observations that cancer stem cells reprogram essential metabolic pathways through integration of extrinsic signals from tumor-infiltrating immune cells and vasculature to promote epigenetic reprogramming, empowering sustained proliferation, self-renewal, and immune evasion. Based on this background, we hypothesize that aging promotes reprogramming of the tumor immune microenvironment and cell autonomous nuclear structural regulation that will inform the development of novel brain tumor treatments. Using spatial transcriptomics and metabolomics of patient tumors and organoids, we will investigate the metabolic alterations within the aging tumor microenvironment to derive multi-modal therapies that disrupt the dynamic growth and survival mechanisms within tumors.
