(545b) Mathematical Modeling of the Extracellular Matrix in Cancer Metastasis

Metastatic cancer accounts for 90% of cancer deaths in the U.S. Early in metastasis, cancer cells detach from the primary tumor site and move through the extracellular matrix (ECM) surrounding the tumor into a blood vessel from which the cancer can spread throughout the body. The ECM is a composite tissue composed primarily of a network of macromolecules including insoluble fibers and fluid-filled pores. Normal ECM serves as a physical barrier to the movement of cells. Cancer cells manipulate the ECM through cellular signaling pathways that activate enzymatic remodeling of the structure of the ECM to facilitate cell migration. ECM remodeling leads to a spatially heterogeneous ECM that changes over time. However, the mechanism of ECM remodeling and the impact of ECM remodeling on physical properties that influence metastatic cell migration are not well understood (Lu, Weaver, & Werb, 2012). Experimental approaches alone cannot decouple the complexities of the many interacting processes during ECM remodeling. Thus, there is a critical need for alternative approaches to understand how ECM composition and structure are modified during metastasis and to determine if ECM properties may be restored to non-metastatic values. Computational models considering simultaneous physiological, chemical, and biomechanical interactions can be developed to enhance quantitative understanding of ECM remodeling in cancer.

In this work, we present a computational model to of ECM remodeling in the early stages of cancer metastasis. The model includes the dynamic reaction and diffusion processes involving ECM-degrading matrix metalloproteinases (MMPs) and ECM-cross-linking lysyl-oxidase (LOX) and their impact on the collagen fibers in the ECM to predict ECM physical properties. This model improves upon existing models for the ECM in tumor metastasis by considering the transport variations due to the heterogeneous medium and the enzymatic reactions of both MMPs and LOX to both degrade and cross-link the ECM in tandem. The concentrations of the MMPs, LOX, and ECM basement membrane and interstitial collagen fibers are tracked with a mechanistic mathematical model that is solved computationally. The simulation results are assessed as to their ability to accurately predict stiffness changes due to ECM remodeling in the metastatic disease state as compared to published experimental data in the literature.

LU, P., WEAVER, V. M. & WERB, Z. 2012. The extracellular matrix: a dynamic niche in cancer progression. J Cell Biol, 196, 395-406.