Multiscale modeling of collective cell migration elucidates the mechanism underlying tumor-stromal interactions in different spatiotemporal scales

Abstract

Metastasis is the pathogenic spread of cancer cells from a primary tumor to a secondary site which happens at the late stages of cancer. It is caused by a variety of biological, chemical, and physical processes, such as molecular interactions, intercellular communications, and tissue-level activities. Complex interactions of cancer cells with their microenvironment components such as cancer associated fibroblasts (CAFs) and extracellular matrix (ECM) cause them to adopt an invasive phenotype that promotes tumor growth and migration. This paper presents a multiscale model for integrating a wide range of time and space interactions at the molecular, cellular, and tissue levels in a three-dimensional domain. The modeling procedure starts with presenting nonlinear dynamics of cancer cells and CAFs using ordinary differential equations based on TGF beta, CXCL12, and LIF signaling pathways. Unknown kinetic parameters in these models are estimated using hybrid unscented Kalman filter and the models are validated using experimental data. Then, the principal role of CAFs on metastasis is revealed by spatial-temporal modeling of circulating signals throughout the TME. At this stage, the model has evolved into a coupled ODE-PDE system that is capable of determining cancer cells' status in one of the quiescent, proliferating or migratory conditions due to certain metastasis factors and ECM characteristics. At the tissue level, we consider a force-based framework to model the cancer cell proliferation and migration as the final step towards cancer cell metastasis. The ability of the multiscale model to depict cancer cells' behavior in different levels of modeling is confirmed by comparing its outputs with the results of RT PCR and wound scratch assay techniques. Performance evaluation of the model indicates that the proposed multiscale model can pave the way for improving the efficiency of therapeutic methods in metastasis prevention.