TY - JOUR
T1 - Plexin-B2 facilitates glioblastoma infiltration by modulating cell biomechanics
AU - Huang, Yong
AU - Tejero, Rut
AU - Lee, Vivian K.
AU - Brusco, Concetta
AU - Hannah, Theodore
AU - Bertucci, Taylor B.
AU - Junqueira Alves, Chrystian
AU - Katsyv, Igor
AU - Kluge, Michael
AU - Foty, Ramsey
AU - Zhang, Bin
AU - Friedel, Caroline C.
AU - Dai, Guohao
AU - Zou, Hongyan
AU - Friedel, Roland H.
N1 - Funding Information:
We thank Aarthi Ramakrishnan for help with data upload, Nicolas Daviaud for experiments with GBM organoids, and Markel Olabarria for the graphic artwork. We also thank investigators Didier Trono and Feng Zhang for depositing plasmids at Addgene that were used for this study. We also would like to thank Patrizia Casaccia and Jialiang Liang for providing CRISPR plasmids. This work was supported by NIH grants R01NS092735 to R.F., R01NS107462 to H.Z., G.D., and R.F., and NCI Cancer Center support grant P30CA196521 to Tisch Cancer Institute.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85100085247&partnerID=8YFLogxK
U2 - 10.1038/s42003-021-01667-4
DO - 10.1038/s42003-021-01667-4
M3 - Article
C2 - 33514835
AN - SCOPUS:85100085247
VL - 4
JO - Communications Biology
JF - Communications Biology
SN - 2399-3642
IS - 1
M1 - 145
ER -