TISSUE STIFFNESS AS A KEY REGULATOR OF BRAIN TUMOR-INITIATING CELLS

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Despite intensive treatment combining surgery, chemotherapy, and radiation, approximately 30% of patients experience fatal recurrence. A major factor underlying treatment failure is the persistence of brain tumor–initiating cells (BTICs), a therapy-resistant population capable of surviving treatment and regenerating the tumor. Understanding the mechanisms that drive BTIC survival and proliferation is therefore critical for developing more effective therapies. MB arises from neural progenitor cells in the cerebellum, which undergo aberrant proliferation in the external granule layer or other cerebellar germinal zones during development. These progenitors are equipped with primary cilia, antenna-like organelles that extend from the cell surface to sense and transduce mechanical and chemical signals, including the sonic hedgehog (SHH) pathway, a key driver of MB growth. Although emerging evidence indicates that primary cilia can have tumor-specific functions, their precise role in MB development remains poorly understood. MB develops within a highly confined anatomical space, bounded by brain parenchyma, meninges, and skull. Our recent work demonstrates that MB tumors are mechanically heterogeneous, with a significantly stiffer periphery compared to a softer tumor core. Strikingly, BTICs in these distinct mechanical niches exhibit differential behaviors: cells at the stiff tumor edge display longer primary cilia, elevated SHH signaling, and enhanced proliferation. These findings reveal a mechanosensitive role of primary cilia in regulating BTIC behavior, providing a new perspective on the regulation of MB growth.