Collaborative Research: Multiscale Modeling and Experimental Study of Blood Cell Interactions with Application to Functionalized Leukocytes Killing Cancer Cells

University Of Notre Dame, Notre Dame IN

Investigators

Abstract

More than 90% of cancer-related deaths are caused by cancer metastasis, the spread of a cancer. In many cases, cancer cells escape from the primary tumor and enter vasculature to form circulating tumor cells (CTCs). CTCs inside blood vessels are able to adhere to vessel walls, and then migrate into tissues, eventually forming micro-metastases. Recently, it was found that when nano-particles coated with certain types of ligands and receptors on their surfaces were injected into the blood, these particles can bind to CTCs and subsequently trigger death of CTCs in the blood. The project concerns using integrated mathematical/computational modeling and experiments to understand quantitatively how this binding process occurs and to identify the roles that ligand-receptor binding and cell-cell interactions play during this process. Results from the project will shed light on designing new nano-particle medical processes for the treatment of cancer metastasis and broadly extend the knowledge of blood cell dynamics. The results are of practical importance in many applications in both bio-engineering and medical communities. The research will also provide interdisciplinary training for students. By combining modeling, simulation and experiments, this project addresses a key biological question of importance to understanding cancer metastasis. What are the key factors that contribute to improving the efficiency of coated nano particles for triggering the death of circulating cancer cells within the vascular system? New three-dimensional multi-scale models will be developed for this study. In this context, a novel sub-model representing cell membrane mechanics, a fluid-structure interaction simulation method and a stochastic ligand-receptor bond bind/unbinding sub-model will be developed and coupled. Atomic force microscopy and micro-fluidic experiments at three spatial scales will be designed for model validation and verifying simulation predictions. The transformative strategy of coupling calibrated multi-scale simulations with experiments will enable testing of novel hypothesized mechanisms by which certain coatings of liposomes kill flowing tumor cells. These goals will be achieved by using an iterative procedure involving development of sub-models, running experiments to validate the sub-models, and then running predictive simulations and designing new experiments for verification of these predictions.