Computational Modeling of Metastatic Cancer Migration Through a Remodeling Extracellular Matrix

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.Chemical Engineerin

Development of a coupled simulation toolkit for computational radiation biology based on Geant4 and CompuCell3D

RL acknowledges support from Consortium for Risk Evaluation and Stakeholder Participation (http://cresp.org). JAG acknowledges support from National Science Foundation grant NSF 1720625 and National Institutes of Health, National Institute of General Medical Sciences grants U01 GM111243 and R01 GM076692, JAG and MS acknowledge support from National Institutes of Health, National Institute of General Medical Sciences grant R01 GM122424.Understanding and designing clinical radiation therapy is one of the most important areas of state-of-the-art oncological treatment regimens. Decades of research have gone into developing sophisticated treatment devices and optimization protocols for schedules and dosages. In this paper, we presented a comprehensive computational platform that facilitates building of the sophisticated multi-cell-based model of how radiation affects the biology of living tissue. We designed and implemented a coupled simulation method, including a radiation transport model, and a cell biology model, to simulate the tumor response after irradiation. The radiation transport simulation was implemented through Geant4 which is an open-source Monte Carlo simulation platform that provides many flexibilities for users, as well as low energy DNA damage simulation physics, Geant4-DNA. The cell biology simulation was implemented using CompuCell3D (CC3D) which is a cell biology simulation platform. In order to couple Geant4 solver with CC3D, we developed a "bridging" module, RADCELL, that extracts tumor cellular geometry of the CC3D simulation (including specification of the individual cells) and ported it to the Geant4 for radiation transport simulation. The cell dose and cell DNA damage distribution in multicellular system were obtained using Geant4. The tumor response was simulated using cell-based tissue models based on CC3D, and the cell dose and cell DNA damage information were fed back through RADCELL to CC3D for updating the cell properties. By merging two powerful and widely used modeling platforms, CC3D and Geant4, we delivered a novel tool that can give us the ability to simulate the dynamics of biological tissue in the presence of ionizing radiation, which provides a framework for quantifying the biological consequences of radiation therapy. In this introductory methods paper, we described our modeling platform in detail and showed how it can be applied to study the application of radiotherapy to a vascularized tumor.PostprintPeer reviewe

Mathematical Modeling of Metastatic Cancer Migration through a Remodeling Extracellular Matrix

The spreading of cancer cells, also known as metastasis, is a lethal hallmark in cancer progression and the primary cause of cancer death. Recent cancer research has suggested that the remodeling of collagen fibers in the extracellular matrix (ECM) of the tumor microenvironment facilitates the migration of cancer cells during metastasis. ECM remodeling refers to the following two procedures: the ECM degradation caused by enzyme matrix metalloproteinases and the ECM alignment due to the cross-linking enzyme lysyl oxidase (LOX). Such modifications of ECM collagen fibers result in changes of ECM physical and biomechanical properties that affect cancer cell migration through the ECM. However, the mechanism of such cancer migration through a remodeling ECM remains not well understood. A mathematical model is proposed in this work to better describe and understand cancer migration by means of ECM remodeling. Effects of LOX are considered to enable transport of enzymes and migration of cells through a dynamic, reactive tumor microenvironment that is modulated during cell migration. For validation cases, the results obtained show comparable trends to previously established models. In novel test cases, the model predicts the impact on ECM remodeling and the overall migration of cancer cells due to the inclusion of LOX, which has not yet been included in previous cancer invasion models

Mathematical Modeling of Metastatic Cancer Migration through a Remodeling Extracellular Matrix

The spreading of cancer cells, also known as metastasis, is a lethal hallmark in cancer progression and the primary cause of cancer death. Recent cancer research has suggested that the remodeling of collagen fibers in the extracellular matrix (ECM) of the tumor microenvironment facilitates the migration of cancer cells during metastasis. ECM remodeling refers to the following two procedures: the ECM degradation caused by enzyme matrix metalloproteinases and the ECM alignment due to the cross-linking enzyme lysyl oxidase (LOX). Such modifications of ECM collagen fibers result in changes of ECM physical and biomechanical properties that affect cancer cell migration through the ECM. However, the mechanism of such cancer migration through a remodeling ECM remains not well understood. A mathematical model is proposed in this work to better describe and understand cancer migration by means of ECM remodeling. Effects of LOX are considered to enable transport of enzymes and migration of cells through a dynamic, reactive tumor microenvironment that is modulated during cell migration. For validation cases, the results obtained show comparable trends to previously established models. In novel test cases, the model predicts the impact on ECM remodeling and the overall migration of cancer cells due to the inclusion of LOX, which has not yet been included in previous cancer invasion models