Johns Hopkins University Physical Sciences-Oncology Center (JHU PS-OC) will explore the mechanical forces in cancer that bolster the tumor metastatic cascade. Metastatic disease is the cause for the preponderance of deaths related to cancer. In fact, relative survival significantly decreases for cancer patients who present with metastases at the time of their diagnosis. This center will bring together experts in cancer biology, molecular and cellular biophysics, applied mathematics, materials science, and physics to study and model cellular mobility and the assorted biophysical forces involved in the metastatic process. One such pressure includes hypoxia located within the tumor. Appropriately, these investigators will investigate the effects of increased levels of hypoxia-inducible factor 1 (HIF-1) on the mechanical properties of the extracellular matrix and evaluate the impact of hypoxia on cellular signaling. Furthermore, state-of-the-art microfabrication facilities will support this center and will construct substrates with micropatterning of extracellular matrix components to uncover the dynamics of cell migration.
Principal Investigator: Denis Wirtz, Ph.D.
Senior Scientific Investigator: Gregg L. Semenza, M.D., Ph.D.
Collaborators: University of Connecticut Health Center, University of Florida, University of North Carolina, Washington University-St Louis
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Denis Wirtz, Ph.D.
Denis Wirtz is professor of Chemical and Biomolecular Engineering and Materials Science in the Whiting School of Engineering and a member of the oncology department at the Johns Hopkins School of Medicine. He earned his Ph.D. in polymer physics at Stanford University. Dr. Wirtz is a recognized expert in cell and molecular biophysics and in the development of new methods grounded in physical principles, including statistical mechanics and polymer physics, to probe and establish the physical mechanisms of cell motility, intercellular adhesion, and microrheology. He has extensive experience in pre-doctoral and postdoctoral training in his own research group and as Director of the HHMI-funded graduate training program at Hopkins in nanotechnology for biology and medicine and of the NCI-funded postdoctoral training program in nanotechnology for cancer medicine, also at Hopkins. These training programs have a complementary relationship to the training activities of the Engineering & Oncology Center. Dr. Wirtz’s research is funded by the NIH (NCI, NIGMS) and the American Heart Association. He is Editor-in-Chief of Cell Health and the Cytoskeleton andserves on the Editorial Boards of Biophysical Journal, Physical Biology, and Cell Adhesion and Migration. As founder and Associate Director of the Johns Hopkins Institute for NanoBioTechnology (INBT), Dr. Wirtz brings expertise to the leadership of the Johns Hopkins Engineering & Oncology Center in the direction of large multidisciplinary research efforts at the interface of biology, engineering, and physics and in the recruitment, training, and retention of a diverse group of students and fellows.
Gregg L. Semenza, M.D., Ph.D.
Gregg L. Semenza is currently the C. Michael Armstrong Professor at Johns Hopkins School of Medicine with appointments in Pediatrics, Medicine, Oncology, Radiation Oncology, Biological Chemistry, and the McKusick-Nathans Institute of Genetic Medicine. He received undergraduate training in Biology at Harvard College; M.D. and Ph.D. degrees from the University of Pennsylvania; pediatrics residency training at Duke University; and postdoctoral training in Medical Genetics at the Johns Hopkins University School of Medicine. He is the founding director of the Vascular Program in the Johns Hopkins Institute for Cell Engineering. Dr. Semenza’s laboratory identified hypoxia-inducible factor 1 (HIF-1), a protein that allows cells to respond to changes in oxygen availability. The purification of HIF-1 in 1995 opened the field of oxygen biology to molecular analysis and has revealed major roles for HIF-1 in many developmental, physiological, and pathological processes. In cancer, HIF-1 plays critical roles in angiogenesis, metabolic reprogramming, stem cell maintenance, EMT, invasion, metastasis, and treatment failure. Dr. Semenza’s laboratory has recently identified several drugs that inhibit HIF-1 and has shown that they block tumor growth and vascularization. Dr. Semenza serves on the editorial boards of Antioxidants and Redox Signaling, Cancer Research, Cardiovascular Research, Circulation Research, Journal of Clinical Investigation, Molecular and Cellular Biology, Molecular Cancer Therapeutics, and Oncogene. He is Editor-in-Chief of the Journal of Molecular Medicine. He has been elected to the Society for Pediatric Research, American Society for Clinical Investigation, Association of American Physicians, and the National Academy of Sciences, USA.
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Project 1 - Functional Interactions between HIF-1 and ECM in Cancer
Project Leaders: Gregg L. Semenza (Johns Hopkins Medical Institute) and Sharon Gerecht (Johns Hopkins University)
This project focuses on analyzing the makeup and physical properties of the extracellular matrix (ECM) 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.
Project 2 - The Physics of Cadherin-Mediated Intercellular Adhesion and 3D Migration in Cancer
Project Leaders: Greg D. Longmore (Washington University-St Louis) and Denis Wirtz (Johns Hopkins University)
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.
Project 3 - Mechanochemical Effects on Tumor Cell Signaling, Adhesion and Migration
Project Leaders: K. Konstantopoulos (Johns Hopkins University) and Martin Pomper (Johns Hopkins Medical Institute)
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.
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Core 1 - PS-OC Imaging Core
Core Leader: J. Michael McCaffery (Johns Hopkins University)
This core has capabilities in epifluorescence/atomic force microscopy, ultra-fast/sensitive dynamic live-cell imaging, and total internal reflectance fluorescence microscopy. In addition, confocal/ multi-photon microscopy, fluorescence correlation spectroscopy, multi-mode scanning electron microscopy, high- vacuum, low-vacuum, and environmental-SEM, and conventional and high-resolution analytical transmission electron microscopy will be utilized. This core will also perform fluorescence-activated cell sorting and analysis.
Core 2 - PS-OC Microfabrication Core
Core Leader: Peter C. Searson (Johns Hopkins University)
This core is housed in a 600-sq. ft. facility and retains the following equipment for photolithography: spin coater; UV lamp; e-beam evaporator; mask aligner; and wet chemical equipment. Adhesive micropatterned surfaces will be used to study the influence of geometry on motility. In another example, microfluidic‐based devices will be fabricated to study the influence of steric forces, extracellular matrix, cell compliance, and adhesiveness on tumor cell migration.
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