Project 1: The Role of Physical Cues in Collective Cell Invasion
A hallmark of cancer is the spread, or metastasis, of cells from the tumor to distant tissues and organs. This invasion eventually causes the death of the patient. Breast cancer cells can travel alone, but they prefer to travel in small clusters. However, little is known about how they travel collectively. This project looks at how the physical forces exerted upon cancer cells by confinement within a tumor can regulate the migration of these cells, both collectively and alone. This project also uses computer modeling and as in vivo imaging to map breast cancer cell migration under different microenvironments.
Project 1 has three aims:
- To develop a an integrated computational and 2D experimental model that examines the role of a specific membrane bound protein (E-cadherin) on group and single breast cancer cell migration under different confined space regimes
- To examine the different means of locomotion of breast cancer cells during primary tumor invasion under different 2D physical microenvironments
- To validate the mechanisms of collective versus single cell migration using a 3D breast cancer cell-culturing environments
Project Leader for Project 1 is Konstantinos Konstantopoulos (ChemBE). Co-investigators are Sean Sun (MechE) and Andrew Ewald and Kenneth Pienta, both of Johns Hopkins School of Medicine.
Project 2: Forces involved in collective cell migration
Pathologic and in vivo experimental evidence tells us that cancer cells like to travel in groups as they leave a tumor site to spread cancer to other parts of the body. In this project, we investigate the forces involved in organizing the collective migration of breast cancer cells in both 2D and 3D environments. We study friction and traction, as well as the active and passive forces present in the cell microenvironment, that is, the extracellular matrix (ECM), in both 2D and 3D cell culture and in vivo. Cell-cell and cell-ECM interactions will be measured. Computational models will help predict experimental results and vice versa.
Project 2 has four aims:
- To determine an integrated experimental and computational model of how tumor cell-intrinsic changes in adhesion influence collective migration
- To determine how changes in the tumor environment affect collective migration of tumor cells
- To determine how cell-cell and cell-ECM forces influence the nature of tumor cell collective migration in clinically relevant primary human breast tumor samples
- To develop a computational model of collective cell migration dynamics in tissues
Project Leader for Project 2 is Denis Wirtz (ChemBE). Co-investigators are Sean Sun (MechE), Gregory Longmore of Washington University in St. Louis, Daniele Gilkes and Pei Hsun Wu, both of Johns Hopkins University.
Project 3: Impact of low oxygen on the migration of sarcoma cells
Low oxygen within a tumor (hypoxia) dramatically increases pulmonary metastasis and result sin poor clinical outcomes. However, little is understood about the critical effects of hypoxia on sarcoma cells and the microenvironment. In this project, we are discovering how primary tumor cells respond to oxygen (O2) in their microenvironment with the goal of better understanding the spread of cancer and identifying new therapeutic targets. We have previously shown that low oxygen leads to greater deposits of the rope-like structural protein collagen in the extracellular matrix (ECM). We think that is ECM remodeling via collagen deposits impacts sarcoma cell migrate, and we hypothesize that oxygen gradients regulate the speed and direction of this migration. In vitro, in vivo and computational models are used in this project.
Project 3 has three aims:
- To determine sarcoma cell and tumor graft responses to spatial oxygen gradients
- To characterize collagen remodeling during sarcoma invasion under hypoxic gradients
- To determine how collagen fiber organization regulates hypoxic invasion and migration
Project Leader for Project 3 is Sharon Gerecht (ChemBE). Co-investigators are Karin Eisinger and Celeste Simon, both of University of Pennsylvania, Sean Sun (MechE), and Charles Wolgemuth, University of Arizona.