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.

Cadherins form a large family of calcium-dependent adhesive proteins involved in morphogenesis, cell differentiation, and neuronal connectivity. Non-clustered δ1 protocadherins form a cadherin subgroup of proteins with seven extracellular cadherin (EC) repeats and cytoplasmic domains distinct from those of classical cadherins. Non-clustered δ1 protocadherins mediate homophilic adhesion and have been implicated in various diseases including asthma, autism, and cancer. Here we present X-ray crystal structures of human Protocadherin-1 (PCDH1), a δ1-protocadherin member essential for New World Hantavirus infection that is typically expressed in the brain, airway epithelium, skin keratinocytes, and lungs. The structures suggest a binding mode that involves antiparallel overlap of repeats EC1 to EC4. Mutagenesis combined with binding assays and biochemical experiments validated this mode of adhesion. Overall, these results reveal the molecular mechanism underlying adhesiveness of PCDH1 and δ1-protocadherins, also shedding light on PCDH1's role in maintaining airway epithelial integrity, the loss of which causes respiratory diseases.

Footpads allow insects to walk on smooth surfaces. Specifically, liquid secretions on the footpad mediate adhesiveness through Van der Waals, Coulomb, and attractive capillary forces. Although the morphology and function of the footpad are well defined, the mechanism underlying their formation remains elusive. Here, we demonstrate that footpad hair in Drosophila is formed by the elongation of the hair cells and assembly of actin filaments. Knockdown of Actin5C caused a malformation of the hair structure, resulting in reduced ability to adhere to smooth substrates. We determined that functional footpads are created when hair cells form effective frameworks with actin filament bundles, thereby shaping the hair tip and facilitating cuticular deposition. We adapted this mechanism of microstructure formation to design a new artificial adhesive device⁠-a spatula-like fiber-framed adhesive device supported by nylon fibers with a gel material at the tip. This simple self-assembly mechanism facilitates the energy-efficient production of low-cost adhesion devices.

Plasmodium falciparum-infected erythrocytes (IE) sequester in the placenta via surface protein VAR2CSA, which binds chondroitin sulfate A (CSA) expressed on the syncytiotrophoblast surface, causing placental malaria (PM) and severe adverse outcomes in mothers and their offspring. VAR2CSA belongs to the PfEMP1 variant surface antigen family; PfEMP1 proteins mediate IE adhesion and facilitate parasite immunoevasion through antigenic variation. Here we produced deglycosylated (native-like) and glycosylated versions of seven recombinant full-length VAR2CSA ectodomains and compared them for antigenicity and adhesiveness. All VAR2CSA recombinants bound CSA with nanomolar affinity, and plasma from Malian pregnant women demonstrated antigen-specific reactivity that increased with gravidity and trimester. However, allelic and glycosylation variants differed in their affinity to CSA and their serum reactivities. Deglycosylated proteins (native-like) showed higher CSA affinity than glycosylated proteins for all variants except NF54. Further, the gravidity-related increase in serum VAR2CSA reactivity (correlates with acquisition of protective immunity) was absent with the deglycosylated form of atypical M200101 VAR2CSA with an extended C-terminal region. Our findings indicate significant inter-allelic differences in adhesion and seroreactivity that may contribute to the heterogeneity of clinical presentations, which could have implications for vaccine design.