TAMI-60. MODULATION OF CELL BIOMECHANICS THROUGH GUIDANCE RECEPTOR PLEXIN-B2 FACILITATES GLIOBLASTOMA INFILTRATION

Infiltrative growth is a major cause of the high lethality of malignant brain tumors such as glioblastoma (GBM). The study of the contribution of biomechanical processes to GBM invasion is an emerging field. We show here that GBM cells upregulate the guidance receptor Plexin-B2 to gain invasiveness by modulating their biomechanical properties. 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 have established Plexin-B2 as a modulator of cell biomechanics that is usurped by GBM cells to gain invasiveness. Ongoing investigations focus on the regulation of the biomechanical properties of cell membrane and cell actomyosin cortex through plexins that provide GBM cells with the mechanical dynamics to penetrate to restricted space.

Plexin-B2 facilitates glioblastoma infiltration by modulating cell biomechanics

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.

First person – Koichiro Maki

ABSTRACTFirst Person is a series of interviews with the first authors of a selection of papers published in the Journal of Cell Science, helping early-career researchers promote themselves alongside their papers. Koichiro Maki is first author on ‘Hydrostatic pressure prevents chondrocyte differentiation through heterochromatin remodeling’, published in JCS. Koichiro conducted the research described in this article while a Post-doctoral fellow in Prof Sara A. Wickström's lab at the University of Helsinki, Finland. He is now an Assistant Professor in the lab of Prof Taiji Adachi at the Institute for Frontier Life and Medical Sciences, Kyoto University, Japan, investigating single-molecular biophysics and cellular biomechanics.

Response of membrane tension to gravity in an approximate cell model

Background Gravity, especially hypergravity, can affect the morphology of membranes, and further influence most biological processes. Since vesicle structures are relatively simple, the vesicle can be treated as a vital model to study the mechanical properties of membranes in most cases. Basic research on membrane tension has become a vital research topic in cellular biomechanics. Methods In this study, a new vesicle model is proposed to quantitatively investigate the response of membrane tension to gravity. In the model, the aqueous lumen inside the vesicle is represented by water, and the vesicle membrane is simplified as a closed, thin, linear elastic shell. Then, the corresponding static equilibrium differential equations of membrane tension are established, and the analytical expression is obtained by the semi-inverse method. The model parameters of the equations are accurately obtained by fitting the reported data, and the values calculated by the model agree well with the reported results. Results The results are as follows: First, both the pseudo-ellipsoidal cap and the pseudo-spherical cap can be used to describe the deformed vesicle model; however, the former can better represent the deformation of the vesicle model because the variance of the pseudo-ellipsoidal cap is smaller. Second, the value of membrane tension is no longer a constant for both models. Interestingly, it varies with the vesicle height under the action of gravity. The closer it is to the substrate, the greater the membrane tension. Finally, the inclination between the tangent and the radial lines at a certain point is nearly proportional to the radius of the cross section in both models. Conclusion These findings may be helpful to study the vesicle model spreading more accurately by taking into account the influence of gravity because it could affect the distribution of membrane tension. Furthermore, it may also provide some guidance for cell spreading and may have some implications for membrane tension-related mechanobiology studies, especially in the hypergravity conditions.