Multiscale Modeling of Cancer Cell Adhesion

Open Access
Author:
Behr, Julie Marie
Graduate Program:
Bioengineering
Degree:
Master of Science
Document Type:
Master Thesis
Date of Defense:
March 27, 2013
Committee Members:
  • Cheng Dong, Thesis Advisor
  • Robert Francis Kunz, Thesis Advisor
  • William O Hancock, Thesis Advisor
Keywords:
  • cellular adhesion
  • computational fluid dynamics
  • binding affinity
  • melanoma
  • cancer cells
Abstract:
The work described in this thesis is one component of a larger-scaled group effort to create a simulation tool that can represent populations of cell types and substrates moving through a flow field and find the probability of aggregates of cells forming. Specifically, this project seeks to define the biochemistry between a circulating melanoma cell and an adherent neutrophil (PMN, in particular), and how the forces acting on the melanoma cell from the surrounding fluid, ability of the cell to deform, and adhesion to the PMN affect the mechanisms leading to melanoma cell metastasis. Metastasis is the process by which a cancerous cell leaves a primary tumor site somewhere in the body, travels through the vasculature, and eventually leaves the vasculature to start a secondary tumor at a distant site. To attempt to define the factors enabling a melanoma cell to metastasize, this biochemistry simulation tool will define the adhesion molecules present on the melanoma and PMN cell surfaces, and calculate their interactions as the melanoma cell moves past the PMN in a flow field. Based on the proximity of the two cells, it may be possible for molecular bonds to form, which apply an adhesive force to the tumor cell. Within the structure of a computational fluid dynamics solver, information is available to define many locations across each cell surface, where individual molecules can be simulated. Within this work, a model will be defined for determining the biochemical rates of reactions between individual molecules, based on their local individual characteristics. All models and computational routines will be made robust enough to allow for future modifications and additional considerations to be incorporated into the model, including an unlimited number of adhesion molecule types to considered, and the ability to redefine the values of parameters to represent different cell types, rather than specifically melanoma cell and neutrophils. For the sake of this model, it is assumed that the neutrophil has already adhered to the endothelial surface, and therefore selectins (which aid in the initial interaction between white blood cells and the endothelium) were not simulated. The melanoma cell in the model expresses ICAM-1 molecules on its surface, and the PMN expresses the B-2 integrins LFA-1 and Mac-1. The PMN is fully rigid, but the melanoma cell is able to move with six degrees of freedom. Computational fluid dynamics is performed using the in-house developed software NPHASE, in which routines describing the biochemistry have been embedded. The biochemistry routines contain both adhesion, representing the ability of molecules to bond and adhere the cells to each other, and repulsion, which represents microvilli, which are not explicitly modeled, pushing the cells apart. Although this project considered melanoma cells and white blood cells, the routines developed in this work can be applied to any cell type of interest, by redefining values of the input parameters. These routines make it possible to run computational fluid dynamics software that incorporates three-dimensional interactions of biological cells.