Glioblastoma stem cell morphotypes convey distinct cell states and clinically relevant functions

Glioblastoma (GBM) is an aggressive brain tumor with a poor prognosis, driven by therapy resistance and invasion into healthy tissue. GBM stem cells (GSCs) play a central role in tumor progression, yet their biology remains poorly understood. Leveraging the similarities between GSCs and embryonic neural progenitor cells, we explore the relationship between GSC morphology and functional states. Combining a custom spatial transcriptomics approach with microscopy in patient-derived GBM organoids, we identified three distinct GSC morphoclasses - elongated, multipolar, and nonpolar - each with a unique transcriptional signature. These morphoclasses correspond to specific behaviors: while elongated cells are invasive, multipolar GSCs form networks conferring chemoresistance. Our findings establish a direct link between stem cell morphology and function, offering new insights into potential therapeutic strategies for invasion and chemoresistance in cancer.