Abstract
Infiltrative growth is a major cause of high lethality of malignant brain tumors such as glioblastoma (GBM). We show here that GBM cells upregulate guidance receptor Plexin-B2 to gain invasiveness. Deletion of Plexin-B2 in GBM stem cells limited tumor spread and shifted invasion paths from axon fiber tracts to perivascular routes. On a cellular level, Plexin-B2 adjusts cell adhesiveness, migratory responses to different matrix stiffness, and actomyosin dynamics, thus empowering GBM cells to leave stiff tumor bulk and infiltrate softer brain parenchyma. Correspondingly, gene signatures affected by Plexin-B2 were associated with locomotor regulation, matrix interactions, and cellular biomechanics. On a molecular level, the intracellular Ras-GAP domain contributed to Plexin-B2 function, while the signaling relationship with downstream effectors Rap1/2 appeared variable between GBM stem cell lines, reflecting intertumoral heterogeneity. Our studies establish Plexin-B2 as a modulator of cell biomechanics that is usurped by GBM cells to gain invasiveness.
Highlights
Infiltrative growth is a major cause of high lethality of malignant brain tumors such as glioblastoma (GBM)
Through a series of mechanosensitive assays as well as molecular studies, we show that GBM cells gain invasiveness by usurping Plexin-B2 signaling to adjust cell biomechanics
To study the mechanisms of diffuse invasion of GBM cells, we utilized a set of patient-derived glioma stem cell lines (GSCs), SD1–SD4, which had been established and maintained in neural stem cell media[22]
Summary
Infiltrative growth is a major cause of high lethality of malignant brain tumors such as glioblastoma (GBM). PlexinB2 adjusts cell adhesiveness, migratory responses to different matrix stiffness, and actomyosin dynamics, empowering GBM cells to leave stiff tumor bulk and infiltrate softer brain parenchyma. GBM cells are known to invade along microvasculature and axon fiber tracts[3,4], but the molecular factors influencing the choice of preferred migratory paths are poorly understood. Our own studies have revealed a link of high expression of Plexin-B2 with poor survival of GBM patients and that Plexin-B2 enhances the migratory capacity of GBM cells[22] These earlier studies were mainly conducted in traditional GBM cell lines cultured in serum-containing medium, i.e., U87MG and LN229, which do not display infiltrative growth in intracranial transplants, and are not wellsuited to study GBM invasiveness. Binding and internalization of angiogenin via Plexin-B2 do not appear to activate Plexin-B2 and its downstrem signaling components as the canonical semaphorin ligands do[23]
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