MS05 - CDEV-07 Part 1 of 2

Modeling cell migration at multiple scales (Part 1)

Wednesday, July 16 at 10:20am

SMB2025 Follow

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

Jared Barber (Indiana University Indianapolis), Luoding Zhu

Description:

Cell migration is inarguably an important process as it plays a major role in embryo development, inflammation, cancer metastasis, wound healing, and other processes. It is an inherently complex multi-scale process. While most molecular parts and corresponding processes involved in cell migration are well-characterized, it is not yet clear how such parts and processes connect and interact in order to produce the migratory motion that we typically see. For this reason, research on cell migration has continued with mathematical modeling yielding major contributions on the way. To explore how part/process interactions affect migration at multiple scales, we have invited speakers to share their work with talks that use mathematical models to explore important factors for cell migration including factors on the subcellular, cellular, and collective migration scales.

Calina Copos

Northeastern University

"Migration modes of small cell groups: which forces govern their emergent movement?"

Collective cell migration is essential to many physiological and pathological processes, yet its classification remains incomplete. Focusing on cohesive cell pairs migrating on flat substrates, we identified two motility modes: the individual contributor (IC) mode, where each cell generates its own traction force dipole, and the supracellular (S) mode, characterized by a single dipole across the pair. Amoeboid Dictyostelium discoideum (Dd) cells predominantly adopt the IC mode, while mesenchymal Madin-Darby canine kidney (MDCK) cells favor the S mode. A two-dimensional biophysical model incorporating cell-cell and cell-matrix adhesions, along with boundary contractility, recapitulated these patterns. The IC mode emerged in Dd-like cells with balanced traction, whereas S mode dominated in asymmetric or MDCK-like pairs, often driven from the rear. Increasing cell-matrix adhesion promoted the IC mode in amoeboid chains but favored the S mode in MDCK-like cells. The model, extended to longer chains, offers a novel theoretical framework to study diverse collective migration behaviors.

Yuehui Xu

Indiana University Indianapolis

"A 3D Viscoelastic Model of Cell Migration with Mechanical and Adhesive Forces"

Gaining a deeper understanding of cell migration can aid in the development of treatments for a wide range of diseases in which it plays a major role, including infection and cancer. To investigate the mechanisms of cell migration and identify key factors that influence migratory behavior, we developed a three-dimensional mathematical model of an HEK 293 cell migrating unidirectionally on a flat substrate. The cell is represented as a network of viscoelastic elements, while focal adhesions are modeled as points on the cell membrane that connect to the substrate using elastic fibers. The model includes forward pushing forces that are typically generated by actin filaments and cause the cell to protrude in the migratory direction. It also includes an internal interconnected set of elements that represent the internal cell structure. We share how our approach is capable of producing results that agree qualitatively with experiment and vary simulation parameters to examine how the cell responds to changes in membrane stiffness, substrate stiffness, internal element elasticity, the number of focal adhesions, and frictional forces. Results suggest the model can be used to consider more physiologically relevant questions in the future such as the effects of different component properties on overall cell migration and forces.

John Dallon

Brigham Young University

"Modeling differential cell motion in the Dictyostelium discoideum slug"

Differential cell motion plays an important role in the front to back pattern formed during the slug stage of the organism Dictyostelium discoideum (Dd). The slug has at least two cell types: prespore cells and prestalk cells. As the slug moves the prestalk cells aggregate to the front of the moving slug while the prespore cells aggregate to the rear. In this talk I will discuss a force based mathematical model where cells attach and detach to one another via discrete adhesions with stochastic dynamics. Using simulations, different strategies that cells could employ are explored which cause differential cell motion leading to this front to back pattern.

David Odde

University of Minnesota

"Modeling the mechanics of glioblastoma progression and treatment."

Effector CD8+ T cells must make cell-to-cell contacts (TCR-MHC-antigenic-peptide-complex) to identify and eliminate cancer cells selectively. This requirement could become a make-or-break factor in the clearance of solid tumors such as glioma, which we focus on in this study, where T cells have to actively search for the cancer cells in the tissue. Several immunotherapies, such as checkpoint blockade and adoptive T cell therapy, have been proposed; however, all of these essentially aim to make T cells better killers, not migrators. In this study, we recognize an equally important factor crucial for their success, i.e., their migration in the tissue. T cells have been assumed to be optimal navigators based on evolutionary reasons, an idea we challenge in this study. Using a combination of ex vivo brain tissue and in vitro assays, we found that T cells, on average, migrated slower than reported in the literature (0.5-2 μm/min, 0.1-1 μm/min vs 6-10 μm/min, 10-30 μm/min) and only modestly faster than cancer cells in a similar setting (0.1-0.2 μm/min), suggesting the need for improvement for effective immune response and immunotherapy. Strikingly, for T cells, the best description was not a single, homogeneous population of superdiffusive walks as previously found but a mix of comparable numbers of sub, normal, and superdiffusive walks, especially at longer time scales. This heterogeneity is advantageous for finding targets of a range of sizes but worse than the single superdiffusive population for finding a fixed target such as a glioma. We investigated the reason for such slow migration. Our T cells, consistent with previous studies, showed evidence of a 'stop-and-go' pattern. We found that hyper adhesive interactions with the perivascular space of blood vessels, the entry point of T cells into the brain, microglia, a major antigen-presenting cell in the brain, and hyaluronic acid, a major ECM protein in the brain, all could explain many, but not all, of the 'stops”. Reducing these 'stops' could increase net T cell migration, potentially an improvement enough to stop the inevitable GBM recurrence under current standard therapy regimens. Next, we used drug-perturbation experiments and high-resolution imaging to unravel the biomechanics of CD8+ T cell migration. We discovered that these T cells are capable of using multiple modes, highlighting their adaptive nature, but often use the familiar motor-clutch mode of cell migration usually reported for cancer cells, but with altered, faster protrusion and focal-adhesion dynamics. To capture these dynamics we developed a momentum-conserving model for hybrid bleb-adhesion-based rapid T cell migration. Together, these results advance our fundamental understanding of T cell migration in the brain, which may inspire better immunotherapies in the future that are focused on making T cells both powerful killers and adept at rapidly locating target cancer cells.

#SMB2025 Follow

Annual Meeting for the Society for Mathematical Biology, 2025.