Our scientific approach is to perform an integrated analysis using biophysical, biochemical, biological, engineering, and computational approaches to gain insight into the cellular, molecular, and physical mechanisms underlying the functional interactions critical for establishing the intracellular and extracellular conditions favorable for metastasis.
We are interested in the role of mechanical forces in cancer tumor growth and the metastatic cascade.
Project 1: Interactions between HIF-1 and ECM
This project focuses on analyzing the makeup and physical properties of the extracellular matrix, the three-dimensional scaffold in which cells live. Normal cells live in a flexible scaffold, but cancer cells create a rigid scaffold that they climb through to invade normal tissue. This project will study how this change occurs and how it is affected by the amount of oxygen to which cancer cells are exposed. Previous studies have shown that cancer cells are deprived of oxygen, which incites them to more aggressively invade the surrounding normal tissues where oxygen is more plentiful. Hypoxia-inducible factor 1 controls the responses of cancer cells to low oxygen. Recently, drugs have been identified that block the action of HIF-1 and inhibit tumor growth in experimental cancer models.
Co-directors: Sharon Gerecht, Ph.D., Gregg Semenza, M.D.,Ph.D
Project 2: Cadherin-Mediated Adhesion in 3D
Cancer cells are able to modulate proteins on the surface almost like a protein brake that allows them to adhere or de-adhere in response to mechanical forces. This project will examine the physical basis for cancer cell adhesion and de-adhesion and how it increases the likelihood that cancer cells will break free, move into the bloodstream and migrate to other tissues.
Co-directors: Denis Wirtz, Ph.D., Greg D. Longmore, M.D., Ph.D.
Project 3: Mechanochemical Effects on Metastasis
This project will investigate the effects of fluid mechanical forces at different oxygen tension microenvironments on tumor cell signaling, adhesion and migration. Fluid flow in and around tumor tissue modulates the mechanical microenvironment, including the forces acting on the cell surface and the tethering force on cell-substrate connections. Cells in the interior of a tumor mass experience a lower oxygen tension microenvironment and lower fluid velocities than those at the edges in proximity with a functional blood vessel, and are prompted to produce different biochemical signals. These differential responses affect tumor cell fate that is, whether a cell will live or die, and whether it will be able to detach and migrate to secondary sites in the body.
Co-directors: Konstantinos Konstantopoulos, Ph.D., Martin L. Pomper, M.D., Ph.D.