A multi-omics analysis of glioma chemoresistance using a hybrid microphysiological model of glioblastoma

Shojaei, Shahla; Amereh, Meitham; Alizadeh, Javad; Dehesh, Tania; Rosa, Simone C. da Silva; Clark, Courtney; Hassan, Misha; Tomczyk, Mateuz; Cole, Laura K.; Hatch, Grant M.; Dolinsky, Vern; Pasco, Chris; Schibli, D.J.; Dhingra, Sanjiv; Srivastava, Abhay; Ravandi, Amir; Vitorino, Rui; Ghavami, Saeid; Akbari, Mohsen

doi:10.1101/2022.10.29.514383

Cited by 3 publications

(2 citation statements)

References 158 publications

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“…However, cell flux is mainly generated according to the interplay between diffusive and adhesive forces, and the directional motion due to chemotaxis. As observed in experimental studies, when cell-cell adhesive forces are dominant, tumors are able to maintain their compact structure, while highly invasive tumors could exhibit a long trace of cell migration [40]. In addition, the composition of the ECM surrounding the tumor is an important stimulus that may switch the invasion mode [14].…”

Section: Model Formulationmentioning

confidence: 99%

Mathematical Modeling of Spherical Shell-Type Pattern of Tumor Invasion

2023

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Cancer cell migration, as the principal element of tumor invasion, involves different cellular mechanisms. Various modes of cell migration including single and collective motions contribute to the invasion patterns. The competition between adhesive cell–cell and cell–matrix forces is a key factor that determines such patterns. In this paper, we study a distinct shell-type mode of tumor invasion observed in brain and breast tumors. In this mode, cells at the outer layer of the tumor collectively move away from the core and form a shell-type shape. Both the core and the shell sustain a sharp interface between cells and the surrounding matrix. To model the preserved interface, we adopted a Cahn–Hilliard-type free energy relation with the contribution of the interfacial stress. This nonconvex form of free energy allows for cells to remain together and preserve the tumor core via adhesive cell–cell forces while separating the core from the surrounding matrix across a continuous sharp interface. In addition, the motion of the shell was modeled using the chemotactic migration of cells in response to the gradient of nutrients. The associated fluxes of cells were implemented in a general form of balance law. A non-Michaelis–Menten kinetics model was adopted for the proliferation rate of cells. The flux of nutrients was also modeled using a simple diffusion equation. The comparison between the model predictions and experimental observations indicates the ability of the model to manifest the salient features of the invasion pattern.

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Section: Model Formulationmentioning

confidence: 99%

Mathematical Modeling of Spherical Shell-Type Pattern of Tumor Invasion

2023

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“…GBM-neuron synaptic interactions in TME have a pivotal role in tumor growth and invasion [36]. We have recently shown that these interactions significantly change the secretome profile of inflammatory and invasion cytokines [37]. More interestingly, the variation in cytokine profile strongly depends on the state of hGBM cells (i.e., non-resistant or TMZresistant) and plays a dual effect.…”

Section: Introductionmentioning

confidence: 99%

Unveiling the role of metabolic rates variation in driving tumor heterogeneity and controlling growth and invasion: insights from an integrated multiscale in-vitro in-silico framework

Akbari

Amereh

Shojaei

et al. 2023

Preprint

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The three-dimensional (3D) structure of solid tumors inherently limits oxygen and nutrient diffusion to deeper cells, resulting in morphological and metabolic variations. Non-physiological levels of oxygen and nutrients within the tumors result in heterogeneous cell populations that exhibit distinct necrotic, hypoxic, and proliferative zones. Among these zonal cellular properties, metabolic rates strongly affect the overall growth and invasion of tumors. Here we report on a hybrid discrete-continuum (HDC) mathematical framework that uses data from a biomimetic three-dimensional (3D) in vitro cancer model to accurately predict cancer growth and treatment response. The mathematical model integrates the continuum field of variables with a discrete approach and incorporates the random walk method for individual cell migration. By tracking the moving boundary of tumoroids, the HDC model separates volumetric growth from invasion. Invasion direction asymmetries were incorporated into the model by involving a randomness component in cellular migration mechanisms when determining the invasion direction. The model also accounts for mechanical and cellular interactions in tumor microenvironment (TME) as key factors characterizing tumor progression. The in-vitro model is composed of tumor organoids (called tumoroids) co-cultured with healthy neurons all embedded within a hydrogel matrix. Results indicated that the HDC model quantitatively predicts volumetric growth and invasion length and tracks the finger-type invasion pattern observed in the in-vitro model. This model has the potential to investigate inhibitory drug effects with the addition of a reaction-diffusion equation and incorporation of targeted signaling pathways in the continuum and discrete modules, respectively.

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Rapid Biofabrication of an Advanced Microphysiological System Mimicking Phenotypical Heterogeneity and Drug Resistance in Glioblastoma

Pun,

Prakash,

Demaree

et al. 2024

Adv Healthcare Materials

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Microphysiological systems (MPSs) reconstitute tissue interfaces and organ functions, presenting a promising alternative to animal models in drug development. However, traditional materials like polydimethylsiloxane (PDMS) often interfere by absorbing hydrophobic molecules, affecting drug testing accuracy. Additive manufacturing, including 3D bioprinting, offers viable solutions. GlioFlow3D, a novel microfluidic platform combining extrusion bioprinting and stereolithography (SLA) is introduced. GlioFlow3D integrates primary human cells and glioblastoma (GBM) lines in hydrogel‐based microchannels mimicking vasculature, within an SLA resin framework using cost‐effective materials. The study introduces a robust protocol to mitigate SLA resin cytotoxicity. Compared to PDMS, GlioFlow3D demonstrated lower small molecule absorption, which is relevant for accurate testing of small molecules like Temozolomide (TMZ). Computational modeling is used to optimize a pumpless setup simulating interstitial fluid flow dynamics in tissues. Co‐culturing GBM with brain endothelial cells in GlioFlow3D showed enhanced CD133 expression and TMZ resistance near vascular interfaces, highlighting spatial drug resistance mechanisms. This PDMS‐free platform promises advanced drug testing, improving preclinical research and personalized therapy by elucidating complex GBM drug resistance mechanisms influenced by the tissue microenvironment.

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A multi-omics analysis of glioma chemoresistance using a hybrid microphysiological model of glioblastoma

Cited by 3 publications

References 158 publications

Mathematical Modeling of Spherical Shell-Type Pattern of Tumor Invasion

Mathematical Modeling of Spherical Shell-Type Pattern of Tumor Invasion

Unveiling the role of metabolic rates variation in driving tumor heterogeneity and controlling growth and invasion: insights from an integrated multiscale in-vitro in-silico framework

Rapid Biofabrication of an Advanced Microphysiological System Mimicking Phenotypical Heterogeneity and Drug Resistance in Glioblastoma

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