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Results for “Biophysics”

Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2019

From spikes to intercellular waves: tuning the strength of calcium stimulation modulates organ size control

Information flow within and between cells depends in part on calcium (Ca2+) signaling dynamics. However, the biophysical mechanisms that govern emergent patterns of Ca2+ signaling dynamics at the organ level remain elusive. Recent experimental studies in developing Drosophila wing imaginal discs demonstrate the emergence of four distinct patterns of Ca2+ activity: Ca2+ spikes, intercellular Ca2+ transients, tissue-level Ca2+ waves, and a global "fluttering" state. Here, we used a combination of computational modeling and experimental approaches to identify two different populations of cells within tissues that are connected by gap junctional proteins. We term these two subpopulations "initiator cells" defined by elevated levels of Phospholipase C (PLC) activity and "standby cells," which exhibit baseline activity. We found that the strength of hormonal stimulation and extent of gap junctional communication jointly determine the predominate class of Ca2+ signaling activity. Further, single-cell Ca2+ spikes are stimulated by insulin, while intercellular Ca2+ waves depend on Gq activity. Our computational model successfully recapitulates how the dynamics of Ca2+ transients varies during organ growth. Phenotypic analysis of perturbations to Gq and insulin signaling support an integrated model of cytoplasmic Ca2+ as a dynamic reporter of overall tissue growth. Further, we show that perturbations to Ca2+signaling tune the final size of organs. This work provides a platform to further study how organ size regulation emerges from the crosstalk between biochemical growth signals and heterogeneous cell signaling states. Author SummaryCalcium (Ca2+) is a universal second messenger that regulates a myriad of cellular processes such as cell division, cell proliferation and apoptosis. Multiple patterns of Ca2+ signaling including single cell spikes, multicellular Ca2+ transients, large-scale Ca2+ waves, and global "fluttering" have been observed in epithelial systems during organ development. Key molecular players and biophysical mechanisms involved in formation of these patterns during organ development are not well understood. In this work, we developed a generalized multicellular model of Ca2+ that captures all the key categories of Ca2+ activity as a function of key hormonal signals. Integration of model predictions and experiments reveals two subclasses of cell populations and demonstrates that Ca2+ signaling activity at the organ scale is defined by a general decrease in gap junction communication as organ growth. Our experiments also reveal that a "goldilocks zone" of optimal Ca2+ activity is required to achieve optimal growth at the organ level.

systems biology↗

bioRxiv2019

Interfacial energy constraints are sufficient to align cells over large distances

During development and wound healing, cells need to form long-ranged ordered structures to ensure precise formation of organs and repair damage. This requires cells to locate specific partner cells to which to adhere. How such cell matching reliably happens is an open problem, particularly in the presence of biological variability. Here, we use an equilibrium energy model to simulate how cell matching can occur with subcellular precision. A single parameter - encapsulating the competition between selective cell adhesion and cell compressibility - can reproduce experimental observations of cell alignment in the Drosophila embryonic heart. This demonstrates that adhesive differences between cells (in the case of the heart, mediated by filopodia interactions) are sufficient to drive cell matching without requiring cell rearrangements. The biophysical model can explain observed matching defects in mutant conditions and when there is significant biological variability. We also demonstrate that a dynamic vertex model gives results consistent with the equilibrium energy model. Overall, this work shows that equilibrium energy considerations are consistent with observed cell matching in cardioblasts, and has potential application to other systems, such as neuron connections and wound repair. Statement of SignificanceCells often need to identify specific neighboring cells, such as during wound repair and forming neural connections. Here, we develop a biophysical model of such cell-cell interactions within the context of the developing heart. We demonstrate that precise cell matching can occur by minimizing the energy costs of interfacial interactions. This model can explain a breadth of experimental observations despite it being a steady-state approximation of a dynamic system. This opens the possibility that such approaches may be applicable to other systems, providing a powerful yet simple framework for understanding cell matching.

systems biology↗

bioRxiv2019

Inferring the collective dynamics of neuronal populations from single-trial spike trains using mechanistic models

Multi-neuronal spike-train data recorded in vivo often exhibit rich dynamics as well as considerable variability across cells and repetitions of identical experimental conditions (trials). Efforts to characterize and predict the population dynamics and the contributions of individual neurons require model-based tools. Abstract statistical models allow for principled parameter estimation and model selection, but possess only limited interpretive power because they typically do not incorporate prior biophysical constraints. Here we present a statistically principled approach based on a population of doubly-stochastic integrate-and-fire neurons, taking into account basic biophysics. This model class comprises an idealized description for the dynamics of the neuronal membrane voltage in response to fast independent and slower shared input fluctuations. To efficiently estimate the model parameters and compare different model variants we compute the likelihood of observed single-trail spike trains by leveraging analytical methods for spiking neuron models combined with inference techniques for hidden Markov models. This allows us to reconstruct the shared input variations, classify their dynamics, obtain precise spike rate estimates, and quantify how individual neurons couple to the low-dimensional overall population dynamics, all from a single trial. Extensive evaluations based on simulated data show that our method correctly identifies the dynamics of the shared input process and accurately estimates the model parameters. Validations on ground truth recordings of neurons in vitro demonstrate that our approach successfully reconstructs the dynamics of hidden inputs and yields improved fits compared to a typical phenomenological model. Finally, we apply the method to a neuronal population recorded in vivo, for which we assess the contributions of individual neurons to the overall spiking dynamics. Altogether, our work provides statistical inference tools for a class of reasonably constrained, mechanistic models and demonstrates the benefits of this approach to analyze measured spike train data.

neuroscience↗

bioRxiv2019

Inorganic salts and compatible solutes help mesophilic bacteria inhabit the high temperature waters of a Trans-Himalayan sulfur-borax spring

While geographically-/geologically-distinct hot springs harbor different levels of microbial diversity, some of them encompass several such taxa which have no strain reported for laboratory growth at >45{degrees}C. We, therefore, hypothesized that native geomicrobial factors could be potent determinants of the microbial habitability of hot spring environments. To test this hypothesis, aquatic microbial communities were revealed metataxonomically, and considered in the context of spring-water chemistry, along the 85-14{degrees}C hydrothermal gradient of a sulfur-boron spring named Lotus Pond located at 4,436 m, within the Puga geothermal area of the Indian Trans-Himalayan region of Ladakh. Water samples were studied from four distinct sites along Lotus Ponds spring-water transit from the vent to an adjacent river called Rulang. Insinuations obtained from geomicrobiological data were tested via pure-culture growth experiments in habitat-inspired media. Microbial diversities were found to be high at all the sample-sites; majority of the genera identified at the 70-85{degrees}C sites were found to have no report of laboratory growth at >45{degrees}C; concurrently, these sample-sites had high concentrations of the kosmotropic solutes boron, lithium, sodium, sulfide, thiosulfate and sulfate, which are known to biophysically stabilize macromolecules. Based on the universal thermodynamic status of these solutes, we conjectured that they may be instrumental in helping mesophiles withstand high in situ temperatures. Corroboratively, growth experiments with a mesophilic, 80{degrees}C-isolate, Paracoccus SMMA_5 showed that at 50{degrees}C and 70{degrees}C, depending on the incubation-time, lithium/boron/sulfate/sodium/glycine-betaine either increases the number of colony-forming units present in the culture or arrests decline of the same. Incubations at 70{degrees}C, followed by fluorescein diacetate staining and flow cytometry, showed that these solutes keep more cells under viable condition than in ready-to-divide state. We concluded that kosmotropes and compatible solutes help mesophiles overcome the chaotropic effects of heat by augmenting such indigenous, entropy-minimizing biophysical mechanisms that apparently trade-off cell division for cell viability.

microbiology↗

bioRxiv2019

Scop3P: a comprehensive resource of human phosphosites within their full context

Protein phosphorylation is a key post-translational modification (PTM) in many biological processes and is associated to human diseases such as cancer and metabolic disorders. The accurate identification, annotation and functional analysis of phosphosites is therefore crucial to understand their various roles. Phosphosites (P-sites) are mainly analysed through phosphoproteomics, which has led to increasing amounts of publicly available phosphoproteomics data. Several resources have been built around the resulting phosphosite information, but these are usually restricted to protein sequence and basic site metadata. What is often missing from these resources, however, is context, including protein structure mapping, experimental provenance information, and biophysical predictions. We therefore developed Scop3P: a comprehensive database of human phosphosites within their full context. Scop3P integrates sequences (UniProtKB/Swiss-Prot), structures (PDB), and uniformly reprocessed phosphoproteomics data (PRIDE) to annotate all known human phosphosites. Furthermore, these sites are put into biophysical context by annotating each phosphoprotein with perresidue structural propensity, solvent accessibility, disordered probability, and early folding information. Scop3P, available at https://iomics.ugent.be/scop3p, presents a unique resource for visualization and analysis of phosphosites, and for understanding of phosphosite structure-function relationships.

bioinformatics↗

bioRxiv2019

Customizable, engineered substrates for rapid screening of cellular cues

Biophysical cues robustly direct cell responses and are thus important tools for in vitro and translational biomedical applications. High throughput platforms exploring substrates with varying physical properties are therefore valuable, however, currently existing platforms are limited in throughput, the biomaterials used, the capability to segregate between different cues and the assessment of dynamic cellular responses. Here we present a multiwell array (3x8) using a substrate engineered with patterns that present topography or rigidity cues welded to a bottomless plate with a 96-well format. Both the patterns on the engineered substrate and the well plate format can be easily customized, permitting systematic and efficient screening of biophysical cues. Here, we demonstrate three multiwell arrays patterned with a variety of topographical and mechanical cues (nano-grooves, soft pillars and nano pillars) tested with three different cell types. Using the multiwell array, we were able to measure cell functionality using analytical modalities such as live microscopy, qPCR and fluorescent immunochemistry. Cardiomyocytes cultured on 5{micro}m grooves showed less variation in electrophysiology and contractile function. Nanopillars with 127 nm height, 100 nm diameter and 300 nm pitch showed improved chondrogenic maintenance from matrix deposition and chondrogenic gene expression. High aspect ratio pillars with an elastic shear modulus of 16 kPa mimicking the cortical bone altered cell adhesion, morphology, and increased expression of osteogenic genes. We have demonstrated the bespoke, controlled and high-throughput properties of the multiwell array that are currently unparalleled in the field today.

bioengineering↗

bioRxiv2019

The Molecular and Structural Asymmetry of the Plasma Membrane

A fundamental feature of cellular plasma membranes (PM) is asymmetric lipid distribution between the bilayer leaflets. However, neither the detailed, comprehensive compositions of individual PM leaflets, nor how these contribute to structural membrane asymmetries have been defined. We report the distinct lipidomes and biophysical properties of both monolayers in living mammalian PMs. Phospholipid unsaturation is dramatically asymmetric, with the cytoplasmic leaflet being [~]2-fold more unsaturated than the exoplasmic. Atomistic simulations and spectroscopy of leaflet-selective fluorescent probes reveal that the outer PM leaflet is more packed and less diffusive than the inner leaflet, with this biophysical asymmetry maintained in the endocytic system. The structural asymmetry of the PM is reflected in asymmetric structures of protein transmembrane domains (TMD). These structural asymmetries are conserved throughout Eukaryota, suggesting fundamental cellular design principles.

cell biology↗

bioRxiv2019

Impact of four common hydrogels on amyloid-β (Aβ) aggregation and cytotoxicity: Implications for 3D models of Alzheimer’s disease

The properties of a hydrogel utilized in 3D culture can influence cell phenotype and morphology, yielding striking similarities to cellular processes that occur in vivo. Indeed, research areas including regenerative medicine, tissue engineering, cancer models, and stem cell cultures have readily utilized 3D biomaterials to investigate cell biological questions. However, cells are only one component of this milieu. Macromolecules play roles as bioactive factors and physical structures. Yet, investigations of macromolecular biophysics largely focus on pure molecules in dilute solution. Biophysical processes such as protein aggregation underlie diseases including Alzheimers disease, which is hallmarked by accumulated neurotoxic amyloid-{beta} (A{beta}) aggregates. Previously, we demonstrated that A{beta} cytotoxicity is attenuated when cells are cultured within type I collagen hydrogels vs. on 2D substrates. Here, we investigated whether this phenomenon is conserved when A{beta} is confined within hydrogels of varying physiochemical properties, notably mesh size and bioactivity. We investigated A{beta} structure and aggregation kinetics in solution and in hydrogels (collagen, agarose, hyaluronic acid and polyethylene glycol) using fluorescence correlation spectroscopy and thioflavin T assays. Our results reveal that all hydrogels tested were associated with A{beta} cytotoxicity attenuation. We suggest that confinement itself imparts a profound effect, possibly by stabilizing A{beta} structures and shifting the aggregate equilibrium toward larger species. It is likely that the milieu that exist within cells and tissues also influences protein-protein interactions; thus, we suggest that it is critical to evaluate whether protein structure, function, and stability are altered in 3D systems vs. ideal solutions and 2D culture.

bioengineering↗

bioRxiv2019

Whole integration of neural connectomics, dynamics and bio-mechanics for identification of behavioral sensorimotor pathways in Caenorhabditis elegans

Computational approaches which emulate in-vivo nervous system are needed to investigate mechanisms of the brain to orchestrate behavior. Such approaches must integrate a series of biophysical models encompassing the nervous system, muscles, biomechanics to allow observing the system in its entirety while supporting incorporations of different model variations. Here we develop modWorm: a modeling framework for the nematode Caenorhabditis elegans using modular integration approach. modWorm allows for construction of a model as an integrated series of configurable, exchangeable modules each describing specific biophysical processes across different modalities (e.g., nervous system, muscles, body). Utilizing modWorm, we propose a base neuro-mechanical model for C. elegans built upon the complete connectome. The model integrates a series of 7 modules: i) intra-cellular dynamics, ii) electrical and iii) chemical extra-cellular neural dynamics, iv) translation of neural activity to muscle calcium dynamics, v) muscle calcium dynamics to muscle forces, vi) muscle forces to body postures and vii) proprioceptive feedback. We validate the base model by in-silico injection of constant currents into sensory and inter-neurons known to be associated with locomotion behaviors and by applying external forces to the body. Applications of in-silico neural stimuli experimentally known to modulate locomotion show that the model can recapitulate natural behavioral responses such as forward and backward locomotion as well as mid-locomotion stimuli induced responses such as avoidance and turns. Furthermore, through in-silico ablation surveys, the model can infer novel neural circuits involved in sensorimotor behaviors. To further dissect mechanisms of locomotion, we utilize modWorm to introduce empirical based variations of intra and extra-cellular dynamics as well as model optimizations on associated parameters to elucidate their effects on simulated locomotion dynamics compared to experimental findings. Our results show that the proposed framework can be utilized to identify neural circuits which control, mediate and generate natural behavior.

neuroscience↗

bioRxiv2019

Multiplexed, bioorthogonal labeling of multicomponent, biomolecular complexes using genomically encoded, non-canonical amino acids

Stunning advances in the structural biology of multicomponent biomolecular complexes (MBCs) have ushered in an era of intense, structure-guided mechanistic and functional studies of these complexes. Nonetheless, existing methods to site-specifically conjugate MBCs with biochemical and biophysical labels are notoriously impracticable and/or significantly perturb MBC assembly and function. To overcome these limitations, we have developed a general, multiplexed method in which we genomically encode non-canonical amino acids (ncAAs) into multiple, structure-informed, individual sites within a target MBC; select for ncAA-containing MBC variants that assemble and function like the wildtype MBC; and site-specifically conjugate biochemical or biophysical labels to these ncAAs. As a proof-of-principle, we have used this method to generate unique single-molecule fluorescence resonance energy transfer (smFRET) signals reporting on ribosome structural dynamics that have thus far remained inaccessible to smFRET studies of translation.

bioengineering↗

bioRxiv2019

Gradients in the cerebellar cortex enable Fourier-like transformation and improve storing capacity

Cerebellar granule cells (GCs) making up majority of all the neurons in the vertebrate brain, but heterogeneities among GCs and potential functional consequences are poorly understood. Here, we identified unexpected gradients in the biophysical properties of GCs. GCs closer to the white matter (inner-zone GCs) had higher firing thresholds and could sustain firing with larger current inputs. Dynamic clamp experiments showed that inner- and outer-zone GCs preferentially respond to high- and low-frequency mossy fiber inputs, respectively, enabling to disperse the mossy fiber input into its frequency components as performed by a Fourier transformation. Furthermore, inner-zone GCs have faster axonal conduction velocity and elicit faster synaptic potentials in Purkinje cells. Neuronal network modeling revealed that these gradients improve spike-timing precision of Purkinje cells and decrease the number of GCs required to learn spike-sequences. Thus, our study uncovers biophysical gradients in the cerebellar cortex enabling a Fourier-like transformation of mossy fiber inputs.

neuroscience↗

bioRxiv2019

Allium roseum L. extract inhibits amyloid beta aggregation and toxicity involved in Alzheimers disease

Allium roseum is an important medicinal and aromatic plant, specific to the North African flora and a rich source of important nutrients and bioactive molecules including flavonoids and organosulfur compounds whose biological activities and pharmacological properties are well known. In the present study, the inhibition of amyloid beta protein toxicity by the ethanolic extract of this plant is investigated for the first time. Preliminary biochemical analyses identified kaempferol and Luteolin-7-o-glucoside as the more abundant phenolic compounds. The effects of A. roseum extract (ARE) on amyloid beta-42 (A{beta}42) aggregation and aggregate cytotoxicity, were investigated by biophysical (ThT assay, Dynamic light scattering and transmission electron microscopy) and cellular assays (cytotoxicity, aggregate immunolocalization, ROS measurement and intracellular Ca2+ imaging). The biophysical data suggest that ARE affects the structure of A{beta}42 peptide, inhibits its polymerization, and interferes with the path of fibrillogenesis. The data with cultured cells shows that ARE reduces A{beta}42 aggregate toxicity by inhibiting aggregate binding to the cell membrane and by decreasing both oxidative stress and intracellular Ca2+. Accordingly, ARE could act as a neuroprotective factor against A{beta} aggregate toxicity in Alzheimers disease.

plant biology↗

bioRxiv2019

Expression and purification of Protease Activated Receptor 4 (PAR4) and analysis with histidine hydrogen deuterium exchange.

Protease activated receptors (PARs) are G-protein coupled receptors (GPCRs) that are activated by proteolyis of the N-terminus, which exposes a tethered ligand that interacts with the receptor. Numerous studies have focused on the signaling pathways mediated by PARs. However, the structural basis for initiation of these pathways is unknown. Here, we describe a strategy for the expression and purification of PAR4. This is the first PAR family member to be isolated without stabilizing modifications for biophysical studies. We monitored PAR4 activation with histidine-hydrogen deuterium exchange (His-HDX). PAR4 has 9 histidines that are spaced throughout the protein allowing a global view of solvent accessible and non-accessible regions. Peptides containing each of the 9 His residues were used to determine the t1/2 for each His residue in apo or thrombin activated PAR4. The thrombin cleaved PAR4 had a 2-fold increase (p > 0.01) in t1/2 values observed for four histidine residues (His180, His229, His240, and His380) demonstrating that these regions have decreased solvent accessibility upon thrombin treatment. In agreement, thrombin cleaved PAR4 also was resistant to thermolysin digestion. In contrast, activation with the PAR4 agonist peptide was digested at the same rate as apo PAR4. Further analysis showed the C-terminus is protected in thrombin activated PAR4 compared to uncleaved or agonist peptide treated PAR4. The studies described here are the first to examine the tethered ligand activation mechanism for a PAR family member using biophysically and shed light on the overall conformational changes that follow activation of PARs by a protease.

biochemistry↗

bioRxiv2019

Niche-inspired synthetic matrices for epithelial organoid culture

Epithelial organoids are now an important tool in fields ranging from regenerative medicine to drug discovery. Organoid culture requires Matrigel, a complex, tumor-derived, extracellular matrix. An alternative completely synthetic matrix could improve culture reproducibility, clarify mechanistic phenomena, and enable applications involving human implantation. Here, we designed synthetic matrices with tunable biomolecular and biophysical properties that allowed us to identify critical gel parameters in organoid formation. Inspired by known epithelial integrin expression in the proliferative niche of the human intestine, we identified an 2{beta}1 integrin-binding peptide as a critical component of the synthetic matrix that supports human duodenal colon and endometrial organoid propagation. We show that organoids emerge from single cells, retain their proliferative capacity, are functionally responsive to basolateral stimulation and have correct apicobasal polarity upon induction of differentiation. The local biophysical presentation of the cues, rather than bulk mechanical properties, appears to be the dominant parameter governing epithelial cell proliferation and organoid formation in the synthetic matrix.

bioengineering↗

bioRxiv2019

Molecular and Circuit Architecture of Social Hierarchy

Social hierarchy is a common organizational structure of animal groups, in which an individuals social status generates an adaptive behavioral state that facilitates interactions with other group members. Although generally stable, the social status of an animal can change, underscoring the plasticity of the underlying neural circuits. Here, we uncover the molecular and biophysical properties of a cortico-thalamic circuit that supports the emergence of hierarchy in mice. We established a robust behavioral paradigm to explore the establishment of hierarchy among groups of unfamiliar males, and identified the mediodorsal thalamus (MDT) and the caudal part of anterior cingulate area (cACC) as brain areas that are differentially activated between dominants and subordinates. Glutamatergic MDT neurons project to inhibitory parvalbumin interneurons of the cACC, and activity levels of both cell types control competitive performance. Synaptic inputs and excitability of MDT neurons undergo dramatic changes according to the animal social status, and single nucleus sequencing identified increased transcription of the voltage gated ion channel Trpm3 in dominant mice, leading to enhanced excitatory transmission in the MDT-cACC circuit. Our data suggest a model in which cellular, molecular and biophysical plasticity in a thalamocortical circuit controls the expression of social status.

neuroscience↗

bioRxiv2019

Diverse muscle spindle firing properties emerge from multiscale muscle mechanics

AO_SCPLOWBSTRACTC_SCPLOWDespite decades of research, we lack a mechanistic framework capable of predicting how movement-related signals are transformed into the diversity of muscle spindle afferent firing patterns observed experimentally, particularly in naturalistic behaviors. Here, a biophysical model demonstrates that well-known firing characteristics of muscle spindle Ia afferents - including dependence on movement history, and nonlinear scaling with muscle stretch velocity - emerge from first principles of muscle contractile mechanics. Further, mechanical interactions of the muscle spindle with muscle-tendon dynamics reveal how motor commands to the muscle (alpha drive) versus muscle spindle (gamma drive) can cause highly variable and complex activity during active muscle contraction and muscle stretch that defy simple explanation. Depending on the neuromechanical conditions, the muscle spindle model output appears to "encode" aspects of muscle force, yank, length, stiffness, velocity, and/or acceleration, providing an extendable, multiscale, biophysical framework for understanding and predicting proprioceptive sensory signals in health and disease.

neuroscience↗

bioRxiv2019

Tuning antiviral CD8 T-cell response via proline-altered peptide ligand vaccination

Viral escape from CD8+ cytotoxic T lymphocyte responses correlates with disease progression and represents a significant challenge for vaccination. Here, we demonstrate that CD8+ T cell recognition of the naturally occurring MHC-I-restricted LCMV-associated immune escape variant Y4F is restored following vaccination with a proline-altered peptide ligand (APL). The APL increases MHC/peptide (pMHC) complex stability, rigidifies the peptide and facilitates T cell receptor (TCR) recognition through reduced entropy costs. Structural analyses of pMHC complexes before and after TCR binding, combined with biophysical analyses, revealed that although the TCR binds similarly to all complexes, the p3P modification alters the conformations of a very limited amount of specific MHC and peptide residues, facilitating efficient TCR recognition. This approach can be easily introduced in peptides restricted to other MHC alleles, and can be combined with currently available and future vaccination protocols in order to prevent viral immune escape. Author SummaryViral escape mutagenesis correlates often with disease progression and represents a major hurdle for vaccination-based therapies. Here, we have designed and developed a novel generation of altered epitopes that re-establish and enhance significantly CD8+ T cell recognition of a naturally occurring viral immune escape variant. Biophysical and structural analyses provide a clear understanding of the molecular mechanisms underlying this reestablished recognition. We believe that this approach can be implemented to currently available or novel vaccination approaches to efficiently restore T cell recognition of virus escape variants to control disease progression.

immunology↗

bioRxiv2025

S1PR3 mediates glial stimulated tumor invasion in response to interstitial fluid flow

Cellular invasion is a primary challenge to complete resection and treatment of glioblastoma, the most aggressive and deadly primary brain tumor. The brain tumor microenvironment actively stimulates glioma invasion through a multitude of cellular, chemical, and biophysical cues. We and others have shown elevated interstitial fluid flow at the tumor border is one such biophysical cue that directly stimulates invasion through tumor-intrinsic signaling and, in other tumor types, priming of cancer-associated stromal cells. It is currently unclear if interstitial flow similarly primes neuroglial cells to promote glioma cell dissemination and can be targeted for therapeutic purposes. Here, we show elevated interstitial flow upregulates expression of sphingosine-1-phosphate receptor 3 (S1PR3) in glial astrocytes and microglia, which drives glioma cell invasion via chemotaxis. Flow-induced expression of glial S1PR3 is tumor-independent and displays a biphasic relationship to fluid shear stress magnitude in vitro and flow rate in vivo. Inhibition of glial S1PR3 in a tissue engineered culture model and orthotopic mouse model abrogates flow-stimulated invasion, demonstrating a tumor-extrinsic approach to limiting glioblastoma progression. Given prior evidence of a pro-inflammatory role for glial S1PR3, identification of S1PR3 as a disease-agnostic marker of flow-stimulated glia may also have therapeutic implications across myriad neuropathologies.

cancer biology↗