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Computational Modeling of Metastatic Cancer Migration Through a Remodeling Extracellular Matrix

Nguyen Edalgo, Yen Thi Hai
The spreading of cancer cells, also known as metastasis, remains a lethal and unstoppable aspect of cancer treatment. Several cancer studies have suggested the remodeling of collagen fibers in the extracellular matrix (ECM) facilitates the migration of cancer cells during metastasis. ECM remodeling refers to the following activities: the ECM degradation caused by the enzyme matrix metalloproteinases (MMPs) and the ECM alignment due to the cross-linking enzyme lysyl oxidase (LOX). Such modifications of the collagen fibers induce changes in physical and biomechanical properties of the ECM that affect cancer cell migration through the ECM. However, the underlying mechanism of how these changes will give way favorably for the directional motility of cancer cells through the pool of collagen fibers in the ECM remains an open question. In this thesis, we employed the art of multiscale modeling of cancer to gain more insight into the complex interplay between metastatic cancer cells and the ECM while it undergoes remodeling. Two in silico models following different modeling approaches are proposed in this work. The first model is developed via the continuum modeling approach. The mathematical model is a system of five coupled partial differential equations (PDEs). The second model is built via the open-source software CompuCell3D upon the insight and framework gained from the continuous model. Modeling method applied in CompuCell3D is a composite of discrete and continuum modeling approach in which cells are treated as discrete while other components such as the ECM and chemicals are described through continuum fields. Both models include the effect of LOX, an enzyme that has not been included in any previous cancer invasion models. LOX are considered to enable transport of enzymes and migration of cells through a dynamic, reaction tumor microenvironment that is modulated during cell migration. Our models thus far have extended other existing relevant models with improved features showing the influential role of LOX as well as MMPs on the remodeling of ECM and metastatic cancer migration.