Glioblastoma (GBM) remains the most aggressive primary brain cancer in adults. Similar to other cancers, GBM cells undergo metabolic reprogramming to promote proliferation and survival. Glycolytic inhibition is widely used to target such reprogramming. However, the stability of glycolytic inhibition in GBM remains unclear especially in a hypoxic tumor microenvironment. In this study, it was determined that glucose-6-phosphatase-α (G6PC/G6Pase) expression is elevated in GBM when compared to normal brain. Human-derived brain tumor initiating cells (BTICs) utilize this enzyme to counteract glycolytic inhibition induced by 2-Deoxy-D-glucose (2DG) and sustain malignant progression. Down-regulation of G6PC renders the majority of these cells unable to survive glycolytic inhibition, and promotes glycogen accumulation through the activation of glycogen synthase (GYS1) and inhibition of glycogen phosphorylase (PYGL). Moreover, BTICs that survive G6PC knockdown are less aggressive (reduced migration, invasion, proliferation, and increased astrocytic differentiation). Collectively, these findings establish G6PC as a key enzyme with pro-malignant functional consequences that has not been previously reported in GBM and identify it as a potential therapeutic target.

Biopolymeric matrices can impede transport of nanoparticulates and pathogens by entropic or direct adhesive interactions, or by harnessing “third-party” molecular anchors to crosslink nanoparticulates to matrix constituents. The trapping potency of anchors is dictated by association rates and affinities to both nanoparticulates and matrix; the popular dogma is that long-lived, high-affinity bonds to both species facilitate optimal trapping. Here we present a contrasting paradigm combining experimental evidence (using IgG antibodies and Matrigel®), a theoretical framework (based on multiple timescale analysis), and computational modeling. Anchors that bind and unbind rapidly from matrix accumulate on nanoparticulates much more quickly than anchors that form high-affinity, long-lived bonds with matrix, leading to markedly greater trapping potency of multiple invading species without saturating matrix trapping capacity. Our results provide a blueprint for engineering molecular anchors with finely tuned affinities to effectively enhance the barrier properties of biogels against diverse nanoparticulate species.

The gastrointestinal (GI) tract is lined with a layer of viscoelastic mucus gel, characterized by a dense network of entangled and cross-linked mucins together with an abundance of antibodies (Ab). Secretory IgA (sIgA), the predominant Ab isotype in the GI tract, is a dimeric molecule with 4 antigen-binding domains capable of inducing efficient clumping of bacteria, or agglutination. IgG, another common Ab at mucosal surfaces, can cross-link individual viruses to the mucin mesh through multiple weak bonds between IgG-Fc and mucins, a process termed mucotrapping. Relative contributions by agglutination versus mucotrapping in blocking permeation of motile bacteria through mucus remain poorly understood. Here, we developed a mathematical model that takes into account physiologically relevant spatial dimensions and time scales, binding and unbinding rates between Ab and bacteria as well as between Ab and mucins, the diffusivities of Ab, and run-tumble motion of active bacteria. Our model predicts both sIgA and IgG can accumulate on the surface of individual bacteria at sufficient quantities and rates to enable trapping individual bacteria in mucins before they penetrate the mucus layer. Furthermore, our model predicts that agglutination only modestly improves the ability for antibodies to block bacteria permeation through mucus. These results suggest that while sIgA is the most potent Ab isotype overall at stopping bacterial penetration, IgG may represent a practical alternative for mucosal prophylaxis and therapy. Our work improves the mechanistic understanding of Ab-enhanced barrier properties of mucus and highlights the ability for mucotrapping Ab to protect against motile pathogens at mucosal surfaces.

A major function of biological hydrogels (biogels) is to serve as barriers against invading pathogens and foreign materials. This review focuses on methods to tune the steric and adhesive barrier properties of biogels at the nanoscale. Altering the biogel mesh spacings that lead to changes in steric obstruction allows for gross exclusion of larger particles but does not provide selectivity with molecular specificity. Enabling direct binding of specific entities to the biogel microstructure introduces specificity yet has very limited breadth, unable to block numerous diverse entities. In contrast, third party modulators that interact with the biogel matrix to enable cross-linking of specific entities to the biogel mesh, or facilitate agglutination of these entities, can robustly tune the barrier properties of biogels against multiple species with molecular specificity without direct chemical modification of the biogel or changes to its microstructure. We review here the design requirements for developing effective third party modulators. The ability to selectively enhance the barrier properties of biogels has important implications for numerous applications including prevention of infection and contraception.

No abstract