Glial Cell Adhesion Molecule (GlialCAM) Determines Proliferative Versus Invasive Cell States in Glioblastoma.

The malignant brain cancer glioblastoma (GBM) contains groups of highly invasive cells that drive tumor progression as well as recurrence after surgery and chemotherapy. The molecular mechanisms that enable these GBM cells to exit the primary mass and disperse throughout the brain remain largely unknown. Here we report using human tumor specimens and primary spheroids from male and female patients that glial cell adhesion molecule (GlialCAM), which has normal roles in brain astrocytes and is mutated in the developmental brain disorder megalencephalic leukoencephalopathy with subcortical cysts (MLC), is differentially expressed in sub-populations of GBM cells. High levels of GlialCAM promote cell-cell adhesion and a proliferative GBM cell state in the tumor core. In contrast, GBM cells with low levels of GlialCAM display diminished proliferation and enhanced invasion into the surrounding brain parenchyma. RNAi-mediated inhibition of GlialCAM expression leads to activation of pro-invasive extracellular matrix (ECM) adhesion and signaling pathways. Profiling GlialCAM-regulated genes combined with cross-referencing to single cell transcriptomic datasets validates functional links between GlialCAM, Mlc1 and aquaporin-4 in the invasive cell state. Collectively, these results reveal an important adhesion and signaling axis involving GlialCAM and associated proteins including Mlc1 and aquaporin-4 that is critical for control of GBM cell proliferation and invasion status in the brain cancer microenvironment. Significance Statement Glioblastoma (GBM) contains heterogeneous populations of cells that coordinately drive proliferation and invasion. We have discovered that the cell adhesion molecule GlialCAM/HepaCAM is overexpressed in proliferative GBM cells within the tumor core. In contrast, GBM cells with low levels of GlialCAM robustly invade into surrounding brain tissue along blood vessels and white matter. Quantitative RNA sequencing identifies various GlialCAM-regulated genes with functions in cell-cell adhesion and signaling. These data reveal that GlialCAM and associated signaling partners, including Mlc1 and aquaporin-4, are key factors that determine proliferative and invasive cell states in GBM.