Biomedical Sciences ETDs

Publication Date

Fall 9-14-2017

Abstract

This dissertation explores the effects of heterogeneity across different biological scales in cancer as well as normal cells. At the tissue scale, we investigated the variability present in the tumor microenvironment and its effect on patient chemotherapeutic outcomes using a mathematical model of drug transport. We found that parameters such as tumor blood perfusion and radius of blood vessel had an impact on the tumor cytotoxicity. This indicated that the physical microenvironment of the tumor is an important regulator of the tumor response to chemotherapy. At the cellular scale, we investigated the heterogeneity present on the membrane landscape of ErbB2 and ErbB3, two receptors that are upregulated in cancer, using a spatial stochastic model of receptor dimerization and phosphorylation. We found that membrane domains played an important role in regulating signaling emanating from this receptor dimer. In our next study, we developed a 3-D spatial stochastic model of pre-BCR, a receptor which is crucial in the development of B lymphocytes and also upregulated in a subset of patients with B-Cell Precursor Acute Lymphoblastic Leukemia, to investigate the effects of ligand independent (tonic signaling) originating from this receptor. We populated our model with single particle tracking data from two different leukemic cell lines which had different dimer off rates and diffusion coefficients, along with experimental measurements. Other important signaling molecules such as Lyn and Syk, which are active in this pathway, were also included in the model. We found that the variability in characteristics between the two cell lines led to differences in downstream signaling events from the receptor. The cell line with the lower dimer off rate formed higher order oligomers and had more overall molecule phosphorylation compared to the other. Thus, this spatial stochastic model was able to shed light on threshold signaling events which take place during tonic signaling.

Keywords

ErbB receptors, Cancer heterogeneity, Pre-BCR, Membrane domains, Spatial stochastic modeling, Tonic signaling

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Jeremy S. Edwards

Second Committee Member

Bridget S. Wilson

Third Committee Member

Diane S. Lidke

Fourth Committee Member

Vittorio Cristini

Fifth Committee Member

Zhihui Wang

Download

Share

COinS