Biology subjects

Motsch, S.

Publications and source records attributed to Motsch, S..

5 recordsLinked to original sources

bioRxiv2023

Modeling Glioma Oncostreams In Vitro: Spatiotemporal Dynamics of their Formation, Stability, and Disassembly

Glioblastoma (GBM), known for its invasive nature, remains a challenge in clinical oncology due to its poor prognosis. Only 5% of patients live past 2 years. The extensive intra-tumoral heterogeneity, combined with aggressive infiltration into surrounding healthy brain tissue limits complete resection and reduces the efficiency of therapeutic interventions. In previous studies using ex-vivo 3D explants and in-vivo intravital imaging, we discovered the existence of oncostreams. Oncostreams are accumulations of nematically aligned elongated spindle-like cells constituted by both tumor and non-tumor cells. We observed a direct correlation between the density of oncostreams and glioma aggressiveness, in genetically engineered mouse glioma models, in high-grade human gliomas, and especially in gliosarcomas. Oncostreams play a pivotal role in the intra-tumoral distribution of both tumoral and non-tumoral cells, potentially facilitating collective invasion of neighboring healthy brain tissue. We further identified a unique molecular signature intrinsic to oncostreams, with a prominent overexpression of COL1A1, MMP9, ADAMts2, and ACTA2 - pivotal genes influencing gliomas mesenchymal transformation and potential determinants of tumor malignancy. COL1A1 inhibition in genetic mouse gliomas resulted in the elimination of oncostreams and induced significant changes in the tumor microenvironment, a reduction in mesenchymal-associated gene expression, and prolonged animal survival. Based on this foundation, we endeavored to model glioma oncostreams in vitro, evaluating the potential of various pharmacologic agents on the formation and organization of oncostreams. Using an optimized workflow, oncostreams were established using GFP+ NPA cells (NRAs\shP53\shATRX) derived from a genetically engineered mouse model utilizing the Sleeping Beauty transposon system. In-depth global and localized statistical analysis employing Julia programming and R Studio based in-house scripts provided insights into the behavior and organization of glioma cells. Our in vitro model led us to probe the impact of factors like cell density, cell morphology, collagen coating, exposure to neurotransmitter agonists, and changes in calcium levels. We also explored interventions targeting specific cytoskeleton structures like non-muscle myosin II B and C, myosin, actomyosin, and microtubules on oncostream formation and organization. In conclusion, our data provide novel information on patterns of glioma migration, which will inform mechanisms of glioma collective invasion in vivo. Through quantitative analysis of these pathologically aggressive and invasive structures, we highlight the importance of potential anti-invasion targets in improving outcomes for GBM patients. Integrating anti-invasive molecules with conventional treatments could significantly enhance clinical benefits. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=195 HEIGHT=200 SRC="FIGDIR/small/571722v1_ufig1.gif" ALT="Figure 1"> View larger version (95K): org.highwire.dtl.DTLVardef@31a40corg.highwire.dtl.DTLVardef@1093c09org.highwire.dtl.DTLVardef@1449e7corg.highwire.dtl.DTLVardef@10892_HPS_FORMAT_FIGEXP M_FIG Dynamics of oncostream structure and cellular motility modulation. This graphical abstract represents the intricacies of the oncostream structure, a proposed model for the collective migration of cancer cells. The central diagram illustrates the oncostream structure, delineated by various treatment conditions radiating outward. Each segment displays a fluorescent micrograph showing the effect of specific inhibitors and compounds on cellular oncostream structure. The array of compounds, including TC-I-15 (21 integrin inhibitor), Collagenase, p-nitro Blebbistatin, Cytochalasin-D, BAPTA-AM, Histamine, Glutamate, 4-Hydroxy acetophenone (4-HAP), Rho-Inhibitor, and Rho-Activator I, are marked on each corresponding segment. Quantitative measures of cellular migration speed, expressed in micrometers per hour (m/h) are noted for each treatment. Notably, the top half of the diagram reveals the oncostreams sensitivity to pharmacological drug treatments, whereas the bottom half shows resistance to these treated conditions. This representation emphasizes the selective effects of pharmacological agents on cancer cell motility within the oncostream framework. C_FIG

cancer biology↗

bioRxiv2022

Scale-free correlations and criticality in explants derived from an orthotopic model of brain cancer

Collective behavior spans several orders of magnitudes of biological organization, ranging from cell colonies, to flocks of birds, to herds of wildebeests. In this work, we investigate collective motion of glioblastoma cells in an ex-vivo experimental model of malignant brain tumors. Using time-resolved tracking of individual glioma cells, we observed collective motion characterized by weak polarization in the (directional) velocities of single cells, with fluctuations correlated over many cell lengths. The correlation length of these fluctuations scales approximately linearly with the total population size, and these scale-free correlations suggest that the system is poised near a critical point. To further investigate the source of this scale-free behavior, we used a data-driven maximum entropy model to estimate the effective length scale (nc) and strength (J) of local interactions between tumor cells. The model captures statistical features of the experimental data, including the shape of the velocity distributions and the existence of long range correlations, and suggests that nc and J vary substantially across different populations. However, the scale and strength of the interactions do not vary randomly, but instead occur on the boundary separating ordered and disordered motion, where the model exhibits classical signs of criticality, including divergences in generalized susceptibility and heat capacity. Our results suggest that brain tumor assemblies are poised near a critical point characterized by scale-free correlations in the absence of strong polarization.

biophysics↗

bioRxiv2020

Oncostreams: Self-organization and dynamics determine spatial heterogeneity and malignant behavior in gliomas

Intra-tumoral heterogeneity and diffuse infiltration are hallmarks of glioblastoma that challenge treatment efficacy. However, the mechanisms that set up both tumor heterogeneity and invasion remain poorly understood. Herein, we present a comprehensive spatiotemporal study that aligns distinctive intra-tumoral histopathological structures, oncostreams, with dynamic properties and a unique, actionable, spatial transcriptomic signature. Oncostreams are dynamic multicellular fascicles of spindle-like and aligned cells with mesenchymal properties, detected using ex vivo explants and in vivo intravital imaging. Their density correlates with tumor aggressiveness in genetically engineered mouse glioma models, and high-grade human gliomas. Oncostreams facilitate the intra-tumoral distribution of tumoral and non-tumoral cells, and the invasion of the normal brain. These fascicles are defined by a specific molecular signature that regulates their organization and function. Oncostreams structure and function depend on overexpression of COL1A1. COL1A1 is a central gene in the dynamic organization of glioma mesenchymal transformation, and a powerful regulator of glioma malignant behavior. Inhibition of COL1A1 eliminated oncostreams, reprogramed the malignant histopathological phenotype, reduced expression of the mesenchymal associated genes, induced changes in the tumor microenvironment and prolonged animal survival. Oncostreams represent a novel pathological marker of potential value for diagnosis, prognosis, and treatment.

cancer biology↗

bioRxiv2019

Self-organization in brain tumors: how cell morphology and cell density influence glioma pattern formation

Modeling cancer cells is essential to better understand the dynamic nature of brain tumors and glioma cells, including their invasion of normal brain. Our goal is to study how the morphology of the glioma cell influences the formation of patterns of collective behavior such as flocks (cells moving in the same direction) or streams (cells moving in opposite direction) referred to as oncostream. We have observed experimentally that the presence of oncostreams correlates with tumor progression. We propose an original agent-based model that considers each cell as an ellipsoid. We show that stretching cells from round to ellipsoid increases stream formation. A systematic numerical investigation of the model was implemented in [R]2. We deduce a phase diagram identifying key regimes for the dynamics (e.g. formation of flocks, streams, scattering). Moreover, we study the effect of cellular density and show that, in contrast to classical models of flocking, increasing cellular density reduces the formation of flocks. We observe similar patterns in [R]3 with the noticeable difference that stream formation is more ubiquitous compared to flock formation. Author summarySelf-organization is the formation of large-scale multicellular patterns that result exclusively from the interactions amongst constituent single cells. To establish the existence of self-organization in brain tumors we used agent-based modeling based on data extracted from static and dynamic genetically engineered mouse glioma models. Implementation of our model in [R]2 identifies the dynamics that lead to formation of flocks (cells moving in a single direction), streams (cells moving in two directions), and cells moving as swarms or scattering. Increasing cellular density reduced formation of flocks and increased the formation of streams both in [R]2 and in [R]3. These results demonstrate the detailed mechanism leading to self-organization in brain tumors. As increasing density of oncostreams correlates with tumor malignancy, we establish a pathophysiological link between self-organization of glioma tumors and glioma malignancy. We propose the dismantling of oncostreams as a new therapeutic approach to the treatment of brain tumors.

systems biology↗

bioRxiv2017

Forecasting crowd dynamics through coarse-grained data analysis

Understanding and predicting the collective behaviour of crowds is essential to improve the efficiency of pedestrian flows in urban areas and minimize the risks of accidents at mass events. We advocate for the development of a & \"crowd forecasting system\"whereby real-time observations of crowds are coupled to fast and reliable models to produce rapid predictions of the crowd movement and eventually help crowd managers choose between tailored optimization strategies. Here, we propose a Bi-directional Macroscopic (BM) model as the core of such a system. Its key input is the fundamental diagram for bi-directional flows, i.e. the relation between the pedestrian fluxes and densities. We design and run a laboratory experiments involving a total of 119 participants walking in opposite directions in a circular corridor and show that the model is able to accurately capture the experimental data in a typical crowd forecasting situation. Finally, we propose a simple segregation strategy for enhancing the traffic efficiency, and use the BM model to determine the conditions under which this strategy would be beneficial. The BM model, therefore, could serve as a building block to develop on the fly prediction of crowd movements and help deploying real-time crowd optimization strategies.

animal behavior and cognition↗