MS02 - ONCO-06

Data-driven integration and modeling of cellular processes in cell motility and cancer progression: Experiments and mathematical models (Part 1)

Monday, July 14 at 3:50pm

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Note: this minisymposia has multiple sessions. The other session is: and Part-2.

Yangjin Kim (Brown University and Konkuk University), Magdalena Stolarska at University of St. Thomas

Description:

Cell motility is a crucial step in metastasis and other detrimental processes in cancer such as cell infiltration in glioblastoma. Cancer is a complex, multiscale process, in which genetic mutations occurring at a sub-cellular level manifest themselves as functional changes at the cellular and tissue scale. Because cell motility plays a large role in cancer regulation, understanding the interactions of individual cells with the tumor microenvironment would provide a foundation to generate new strategies in cancer treatments. In particular, understanding the effect of the microenvironment on the signal transduction pathways of individual cells can improve cancer therapies by allowing one to target the specific biochemical pathways that are associated with the disease. Therefore, the main aim of this session is to discuss recent advances and challenges in modelling cell motility, tumor growth, and the development of new therapeutic strategies. Specific goals of the session include: (i) analyzing both computational and analytical solutions to mathematical models of tumor growth and its interaction with the microenvironment, (ii) improving our biochemical/biomechanical understanding of fundamental mechanism of cell motility in the context of cancer progression, and (iii) comparing experimental data and projecting new experimental ideas that allow us to better understand cellular processes that lead to the design of data-driven platforms for clinical diagnosis.

Magda Stolarska

University of St. Thomas

"A mathematical model of active cortical stress generation and its effect on cell movement"

When moving through a confined, fibrous extracellular environment, many cells use an amoeboid mode of cellular motility. In particular, it is well known that cancer cells can undergo a mesenchymal-amoeboid transition under certain conditions. Amoeboid motility is characterized by weak adhesions to the extracellular environment, a rounded morphology, and flow of the actin cortex. A related, yet simpler, mode of cell motility is cellular swimming. In eukaryotic cell swimming, it is known that active deformation of the cortex induces attachment-free movement through a fluid, but much of the details of this process are not well understood. In this talk, I will present a mathematical model that aims to begin investigating how variability in actomyosin activity in the cortex, properties of the cortex-membrane (ERM) attachment proteins, and the mechanical properties of the microenvironment affect cell movement through a fluid. The hybrid model presented models the intra- and extra-cellular fluid as a continuum and treats the membrane and cortex and a discrete system of connected segments and nodes. By using the finite element method to solve the model equations, we are able to analyze how varying various properties of this system affects cellular swimming velocities.

Dumitru Trucu

University of Dundee

"Advancements in multiscale modelling for glioblastoma: emergence of 'on-the-fly' non-local isotropic-to-anisotropic transition in cell population transport"

Despite all recent in vivo, in vitro, and in silico advances, the understanding of the genuine biologically multiscale process of solid tumour invasion remains one of the greatest open questions for scientific community. In this talk we present recent mathematical multiscale moving boundary modelling advancements for solid tumour invasion, with special focus on glioblastoma progression. We focus on enhancing the mathematical modelling for key aspects of the dynamic interactions that the migratory cancer cells population and the accompanying matrix degrading enzymes (MDEs) have with the extracellular matrix (ECM) components, and, in particular, with the ECM fibres. These are complex interactions enabled by a complicated series of integrated multiscale systems, which are at least two-scale in nature and share (and contribute to) the same tumour macro-dynamics (i.e., tissue-scale dynamics) but have independent-in-nature micro-dynamics (i.e., cell-scale dynamics), and despite previous modelling progress, these deserve significant renewed research efforts. Specifically, this talk we seek to address: (1) the enhancing effect of the interfacial presence of ECM fibres on the macro-scale tumour boundary movement; (2) a new non–local “go-or-grow” perspective on the motility of cancer cel population; and (3) the emerging “on-the-fly” non–local isotropic – to – anisotropic transition in the diffusive cell population transport. Mathematical formulations for all these aspects are proposed analytically and then explored computationally and discussed in the context of glioblastoma progression.

Padmini Rangamani

University of California San Diego

"Modeling collagen fibril degradation as a function of matrix microarchitecture"

Collagenolytic degradation is a process fundamental to tissue remodeling. The microarchitecture of collagen fibril networks changes during development, aging, and disease. Such changes to microarchitecture are often accompanied by changes in matrix degradability. In a matrix, the pore size and fibril characteristics such as length, diameter, number, orientation, and curvature are the major variables that define the microarchitecture. In vitro, collagen matrices of the same concentration but different microarchitectures also vary in degradation rate. How do different microarchitectures affect matrix degradation? To answer this question, we developed a computational model of collagen degradation. We first developed a lattice model that describes collagen degradation at the scale of a single fibril. We then extended this model to investigate the role of microarchitecture using Brownian dynamics simulation of enzymes in a multi-fibril three dimensional matrix to predict its degradability. Our simulations predict that the distribution of enzymes around the fibrils is non-uniform and depends on the microarchitecture of the matrix. This non-uniformity in enzyme distribution can lead to different extents of degradability for matrices of different microarchitectures. Our simulations predict that for the same enzyme concentration and collagen concentration, a matrix with thicker fibrils degrades more than that with thinner fibrils. Our model predictions were tested using in vitro experiments with synthetic collagen gels of different microarchitectures. Experiments showed that indeed degradation of collagen depends on the matrix architecture and fibril thickness. In summary, our study shows that the microarchitecture of the collagen matrix is an important determinant of its degradability.

Noe Mercado

Warren Alpert Medical School, Brown University

"Impact of Cytomegalovirus on Glioblastoma progression"

Background: Glioblastoma (GBM) is the most common primary malignant brain tumor and has no effective treatments. Human Cytomegalovirus (HCMV) has been implicated in GBM progression and antiviral drugs like Cidofovir (CDV) have promising activity in GBM. Previously we reported that in our established syngeneic GBM mouse model perinatally infected with murine cytomegalovirus significant reduction in overall survival compared to uninfected controls. Treatment with CDV improved survival in infected mice and inhibited MCMV reactivation as well as tumor angiogenesis. However, the molecular mechanisms of antiviral drug treatment on GBM have not been studied. Results: Here we show that GBM patient-derived glioma stem cells (GSCs) are highly permissive to HCMV infection compared to established GBM lines commonly used in in vitro (U-373). Neuronal cells that are found in the tumor microenvironment also have high permissiveness to infection although viability significantly decreased post infection. Treatment with antiviral drug Brincidofovir (BCV), a lipid prodrug of cidofovir, significantly reduced viral infection but did not directly induce GBM cell killing. When cells were treated with standard of care (SOC) therapy comprising irradiation (6Gy) and temozolomide (TMZ), resistance to cell death was observed in infected GSCs. This phenotype was reversed by treatment with BCV in a dose-dependent manner. These observations suggest that HCMV induces resistance to SOC in GSCs which may promote GBM progression, and this may be a target of antiviral therapy. Proteomic analysis of infected GSCs revealed upregulation of several pro-tumorigenic proteins including Structural Maintenance of Chromosome 4 (SMC4), WD repeat domain 5 (WDR5) and thymocyte selection associated high mobility group (TOX). Interestingly upon antiviral drug treatment these proteins were no longer upregulated and instead several were significantly downregulated after BCV treatment. Conclusions: Together these data suggest that HCMV may promote tumorigenesis in part due to the glioma stem cell niche. After infection these glioma stem cells are more resistant to chemoradiotherapy which can be overcome by antiviral drug (BCV) treatment. These data provide mechanistic evidence for the role of HCMV in GBM and support ongoing research into antiviral drug approaches in the clinic.

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Annual Meeting for the Society for Mathematical Biology, 2025.