Plexin-B2 facilitates glioblastoma infiltration by modulating cell biomechanics

• DOI: 10.1038/s42003-021-01667-4
• Publication Date: 2021-01-29T11:19:10Z
• Authors: Yong Huang; Rut Tejero; Vivian K. Lee; Concetta Brusco; Theodore Hannah; Taylor B. Bertucci; Chrystian Junquei...; Igor Katsyv; Michael Kluge; Ramsey Foty; Bin Zhang; Caroline C. Friedel; Guohao Dai; Hongyan Zou; Roland H. Friedel
• Keywords: Male; QH301-705.5; Telomere-Binding Proteins; Nerve Tissue Proteins; Mice, SCID; Semaphorins; Article; Shelterin Complex; Cell-Matrix Junctions; 03 medical and health sciences; Cell Movement; Cell Line, Tumor; Animals; Humans; Neoplasm Invasiveness; Biology (General); Adaptor Proteins, Signal Transducing; Mice, Inbred ICR; 0303 health sciences; Brain Neoplasms; Biomechanical Phenomena; Gene Expression Regulation, Neoplastic; Glioblastoma; Signal Transduction; Transcription Factors

AbstractInfiltrative 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.