P02.20.A IRON-DRIVEN MESENCHYMAL TRANSITION ENHANCES INVASION IN GLIOBLASTOMA

Abstract BACKGROUND Iron metabolism is essential for tumor proliferation and survival, yet its dysregulation can drive mutagenesis and tumor evolution. Glioblastoma (GBM) stem-like cells tolerate high reactive oxygen species (ROS) levels and exploit iron-rich environments to support unchecked proliferation. We hypothesize that iron influx through the leaky GBM vasculature creates a ROS- and iron-rich tumor microenvironment (TME), fostering a mutagenic niche that promotes a mesenchymal transition and enhances tumor invasion. MATERIAL AND METHODS We conducted single-nucleus RNA sequencing on in-house GBM samples to assess the interplay between iron metabolism and invasion programs. In vitro validation was performed using patient-derived GBM cell lines exposed to exogenous iron. To model TME influences, we employed ex vivo human cortical slice cultures to track three-dimensional GBM invasion, proliferation, and tissue colonization over six days. Findings were further validated using publicly available GBM datasets. RESULTS Transcriptomic analysis revealed enrichment of iron-handling proteins (FTH1, FTL) specifically in highly invasive tumor cells. Iron supplementation increased migration and invasion rates by 2.5-fold (p<0.01) and augmented cluster formation in human ex vivo models. Notably, iron-exposed GBM cells exhibited upregulation of mesenchymal markers (CD44, CHI3L1) alongside iron metabolism genes. In the TME, microglia serve as primary iron reservoirs and potentially facilitated iron transfer to tumor cells via ferroportin-mediated export. CONCLUSION Our data uncovers iron dysregulation within the GBM TME as a key driver of mesenchymal transition and invasive tumor behavior. Targeting microenvironmental iron handling pathways, including microglial ferroportin-mediated iron export, emerges as a promising therapeutic avenue to mitigate GBM progression.