Collaborative Research: Modeling Stochastic Spatial Effects in Epithelial Mesenchymal Transformation, Signaling, and Cell Migration and Invasion

William Marsh Rice University, Houston TX

Investigators

Abstract

It has been discovered that cancerous tumors are capable of enrolling support from "normal" cells of the host organism. Some of these cells are then reverting to normally suppressed behaviors such as mobility and invasion as well as resistance to cell death. In the process, cells also lose ability to organize themselves into sheets and other structures common in normal tissue. This process is known as the epithelial-mesenchymal transformation (EMT). Motivated by this example, the investigators developed an experimental model of one type of EMT and, along with biological experiments, are now able to reproduce some features of EMT in computers, i.e., to model the EMT mathematically. In the current project, the investigators pursue research based on these preliminary results. These experiments and computer models give rise to a better understanding of signaling processes and, in some cases, leads to better predictions of the effect of treatments on behavior of cancer cells, thus helping advance the fight against cancer. In more technical terms, the objective of the proposed research is multidisciplinary and multiscale analysis of the Epithelial Mesenchymal Transformation (EMT). EMT is the process by which epithelial cells reversibly lose baso-apical polarity and cell-cell junctions, acquiring plasticity, mobility, invasivity, stem-cell characteristics, and resistance to apoptosis. This mechanism is important in embryogenesis, as well as in wound healing and in cancer metastasis. The investigators are particularly interested in the role of NF-kB and p53 and their crosstalk in cancer-related (type III) EMT. The goal is to build a mathematical model that will relate signal transduction pathways to changes in cell behavior, focusing on observing and modeling cell motility. An experimental system is developed to measure motility and proliferation using the new Cell Tracker software and Lineage Tracker for quantitation. Gene expression and flow cytometry measurements will be included. Preliminary data show activation of the NFkB pathway increases motility. Results of the project can be used to reduce cellular invasion in epithelial malignancies, or sensitize cancer cells to chemotherapeutic agents. Although the current study has a basic nature, the resulting insights will inform biomedically oriented applications.