Cell migration in tumor microenvironments plays a crucial role in disease progression and treatment efficacy. Recent experimental studies reported variations in cell migration through changing microenvironments depending on phenotypes, chemokines, and collective cell structures. Here, we developed two agent-based models (ABMs) with Compucell3D (a cellular Potts lattice-based model) to simulate the physiological response and identify the effects of random and directed cell migration in response to chemokines and the formation of invasive and non-invasive cell structures in response to secreted chemoattractants. The first ABM simulates the dynamics of the transwell cell migration assay. The model shows a 3D slice space of the transwell device with 200 moving agents. With periodic boundary conditions applied to vertical surfaces of the domain, the model can simulate in vitro transwell experiments where cells have realistic biomechanics of neighboring cells and tissue-mimic biomaterials. The group of moving agents mimics cells with Brownian motion, located above a solid plane representing a collagen-coated transwell membrane. The solid plane contains randomly distributed pores that simulate the realistic structure of the transwell membrane with the same level of pore density. Chemokines are initiated from the bottom of the transwell below the membrane and can diffuse upwards to generate a concentration gradient. Several factors, including chemical concentrations, diffusion coefficients, chemotactic potential coefficient, an external potential energy term, and a contact energy term are included with a direct connection to published data. The randomized external potential energy simulates the intrinsic Brownian motion of cells and drives cells to move through membranes in the negative control group without chemokines. We observed that larger external potential energy can induce more cells to migrate through the membrane. Thus, we calibrate this energy term with negative control group data from different cell lines (e.g., Panc1, MiaPaCa2, and HPAFII). Our simulated results also predicted variations in cell migration with cell density and pore density of the membrane in the negative control groups. Next, we are extending the model to investigate the effects of chemokine concentrations and diffusion in the negative control groups. The second ABM simulates and compares the migration dynamics of invasive and non-invasive phenotypes of cancer cells. The model incorporates key biological factors governing cancer cell migration, including cell-cell, cell-matrix interactions, cell division, chemoattractant secretion, and phenotypic differences. An experimental study of MDA-MB-231 BRCA cells cultured in a 3D COL1 reported heterogeneous migration phenotypes: an invasive phenotype that forms network structures and a non-invasive phenotype that forms spheroid structures. These multicellular phenotypes depend on the secretion of chemoattractant by cells. Our simulated results predicted the formation of network structures of cells with a higher secretion rate and spheroid structures of cells with a lower secretion rate. The model also predicted the effect of contact energy and cell elongation in the formation of collective structures from a single cell. By integrating experimental data and our ABM, we aim to elucidate the distinct migratory strategies adopted by cancer cells exhibiting network and spheroid structures for invasive and non-invasive phenotypes. In the future, we will implement these validated mechanisms and physiological properties to new ABMs to simulate cancer pathology and therapy inside the body, considering cells, chemokines, and tumor microenvironments. The long-term goal is to develop immunotherapies that alter the tumor immune microenvironment to control cancer.

Acknowledgments: This work was supported by R35 GM133763 and the University at Buffalo. MBD is supported in part by R01 CA226279.

Disclosures: MBD has ownership and financial interests in ProteinFoundry, LLC and Xlock Biosciences, LLC.