University of Pennsylvania PS-OC
Physical Science Oncology Center at Penn
This PS-OC focuses on physical changes of tissues, cells, and nuclei that contribute to cancer growth and possibly initiation.
As tumor cells invade and displace normal cells, the tissue often changes physically, frequently becoming stiffer, sometimes softer, often heterogeneously. Physical changes sometimes occur even before the cancer is detectable.
Primary liver cancer appears representative as it almost always arises in the setting of end-stage liver fibrosis, termed cirrhosis, with various causes including excess alcohol consumption. Liver stiffness is now being measured clinically in living patients, and initial studies already show patients with stiffer livers are far more likely to develop liver cancer within a few years.
The PS-OC is developing widely applicable techniques for measuring and understanding the mechanical properties and molecular makeup of a patient’s tumors, cells, and nuclei for comparison to adjacent normal tissue.
Cancer experts in the PS-OC are integrated with physical scientists and engineers who conduct a diversity of biophysical experiments from tissue scale down to single molecules. Theorists in the PS-OC take multi-scale modeling approaches to clarifying and predicting biophysical phenomena.
Supercomputer modeling is used daily around the world to predict the weather, and so applying such tools of modern physics to cancer dynamics could eventually prove crucial to prognosis, provided the physics of tumor microenvironment is part of the calculation.
Many tumors are first detected as hard lumps of stiff tissue in what clinician’s refer to as a physical exam. Even though the liver is under the rib cage and difficult to touch, physical methods such as ultrasound can provide quantitation. More than 30,000 people in the United States are diagnosed each year with primary liver cancer according to the American Cancer Society, and the five-year survival rate is less than 15 percent. New methods to improve early detection and treatment of the disease are clearly needed, and rigorous understanding of disease processes will be essential to progress.
How tumors become palpably distinct masses and how such physical changes contribute to tumor growth are the general questions to address. Methods range from single molecule imaging and isolated nucleus manipulation to tissue microrheology in foundational studies of molecular and tissue profiles that are central to today’s Precision Medicine approaches to patient disease.
The deep scientific issue driving the PS-OC research agenda is rooted in an emerging awareness that tumor microenvironments contribute to how cell sub-populations are selected to grow and further evolve. Charles Darwin pioneered similar concepts for evolutionary adaptation of animals, with his classic example of finches developing different shapes of beaks over generations to optimize foraging on different islands where – for example – only large, hard seeds are available versus islands with insects hiding within cracks in tree bark.
In solid tumors such as liver cancer, it has long been known that stiff, scar-like collagen bundles accumulate in nearby normal tissue, much like what occurs when tissue is injured. Recent research has also shown that a physical stiffness of microenvironments can in turn promote the multiplication of cells and can influence what genes are expressed by cells to help evolve and spread the cancer.
An overall hypothesis of this PSOC is that differences between cells in a given population can arise due to physical properties of microenvironments, and that mutations might also be caused directly by physical properties of microenvironments to drive cancer.
Project 1: Pre-malignant Stiffening in Liver Cancer
This project pursues novel hypotheses about physical mechanisms of pre-malignant stiffening in primary liver cancer and will elaborate their impact on liver cell function and malignant transformation.
Specialized rheological measurements of freshly isolated human hepatocellular carcinoma (HCC) under compression/tension support the hypothesis that HCC is stiffer than normal not only when measured in shear but even more so in compression. Higher pressures in tumors can result from blood and fluid pressure as well as expansion stress of proliferating cells. No other tumors have been studied in shear under pressure, which is a major omission because pressure is broadly relevant to interpreting any in situ clinical measurements and could, coupled with flows, impact any cancer.
The PS-OC team was the first to publish the important finding that liver stiffness increases before fibrosis develops, and stiffening appears to drive fibrosis. They were also first to explain how matrix stiffness drives proliferation for cancer cell lines, which prompts a key hypothesis that stiffness promotes proliferative replication and transformation.
Project 2: Membrane Transduction in Liver Cancer
This project pursues a novel, systems-level hypothesis of membrane mechanotransduction that bidirectionally couples biophysical effects of the HCC microenvironment to numerous signaling pathways governing cell decisions and fate.
The membrane is how a cell senses physical properties of its surrounding environment, but that information must be transmitted inside the cell for it to change its molecular machinery. The membrane biophysics field is highly advanced with modeling already driving experiments. Membrane bending, tension, and stretching are all well-established biophysical quantities, but their role(s) in cancer cell function are grossly under-studied.
HCC membranes – with altered lipid profiles and perturbed signaling pathways – will be greatly advanced by complementary theory and experiments. PS-OC researchers are visualizing mechanotransduction signaling with super-resolution microscopy (a method that earned its inventors a Nobel Prize in 2014).
Probing down to the single-molecule level will provide sufficient structural information to enable realistic simulations on supercomputers, which can be used to generate predictions of molecular functions.
Project 3: Nuclear Rheologyin Liver Cancer
This project focuses on how the shape of the cell’s nucleus changes as part of a response to altered microenvironments.
The nucleus of course contains and confines a cell’s DNA, and physicists decades ago were not only pioneers in determining the double helix structure of DNA (Francis Crick) but also in discovering the links between aging, cancer, and accumulation of DNA damage (from Atomic Energy physicists).
PS-OC investigators are pursuing a new causation hypothesis, namely that tissue rigidity contributes to genome instability and cancer for dynamically migrating and/or stressed nuclei. The team aims to understand nuclear rheology and DNA stability down to the single molecule level by combining novel single-cell measures of nuclear rheology, unique 3D-migration microdevices that stress the nucleus, and DNA damage analyses.
HCC tumors exhibit atypical nuclei, and initial profiling suggests changes in key nucleoskeletal proteins called lamins that determine nuclear rheology. Lamins are altered in many cancers as well as in aging.
The PS-OC team was the first to relate nuclear rheology changes to cell invasion and survival across micropores and also in grafted tumors. Migration in 3D through stiff tissues and across basement membranes affects nuclear morphology and is expected to impact DNA stability and cell function.
Core 1: Liver Cancer Tissue
This core isolates and provides standard characterizations of fresh HCC tissue and cell samples from patients. It also develops and provides rodent and xenograft models of human cells in both liver and non-hepatic sites. It is also performing additional studies of an established mouse model of HCC. PS-OC projects use the tissue samples and animal models.
Members of this core are all physician-scientists with expertise in liver biology and/or HCC. They also serve as invaluable clinical resources for the PS-OC, and work closely with the broader clinical oncology and hepatology communities at Penn to incorporate PS-OC findings into many other basic research and clinical studies.
Importantly, the core serves as a source of clinical knowledge and expertise for all PS-OC investigators.
Core 2: Theories of Liver Cancer
This core develops and applies key Soft Matter Physics Theories across PS-OC projects. Soft Matter Theory approaches capture the essence of our major physical sciences perspective.
The Nobel Laureate PG deGennes ‘wrote the book(s)’ on this approach that has proven essential to describing and predicting in molecular-scale terms the physical responses of all manner of polymers and colloids – which is the essence of biochemistry. The impact on cell and tissue biology is only now being realized through studies such as those proposed here.
PS-OC projects require help with theory on stiffness effects of rigid, oriented matrix fibers in shear under compression. The PS-OC also treats tissue as an active soft solid, rather than as a traditional passive soft solid. Active matter systems are many-body systems that are maintained out of equilibrium by energy injected at the microscopic or molecular scale.
The PS-OC integrates theory from this core with continuum models of membrane dynamics under stress when different proteins (or lipids) incorporate or bind (soft versus stiff, and normal versus disease). It also needs theories of 3D nuclear migration to predict stress hotspots for observed nuclear lamina segregation, and additional theories for stretched random walks of DNA breaks will be crucial for PS-OC investigators.
These inherently multiscale concepts are not just novel but also key to understanding liver mechanics, and the biochemical mechanisms that affect liver mechanics at the tissue scale, linking liver mechanics to HCC. These concepts will impact studies of all tissue mechanics.
Education and Outreach Unit
This PS-OC is working to educate the next generation of cancer researchers in the physics of cancer through seminars, lectures (including informal interactions with speakers), and Summer Talks given by PS-OC trainees. It also disseminates research and educational resources via Penn Canvas and the PS-OC website.
Dennis E. Discher, Ph.D.
University of Pennsylvania
Dr. Dennis E. Discher, the Project Director for the PS-OC, is the Robert D. Bent Professor at Penn with appointments in Engineering and Applied Science as well as in the Graduate Groups of Physics, Pharmacology, and Cell & Molecular Biology. He has had joint grants and publications with faculty in all of the participating Schools, including several of the Center Investigators. He received a Ph.D. from the University of California, Berkeley in 1993, was an NSF International Postdoctoral Fellow in computational biophysics at Simon Fraser University and the University of British Columbia, and has been on the Penn faculty since 1996. He is an elected member of the US National Academy of Engineering – Bioengineering Section.
He has trained more than 50 Ph.D. students and postdoctoral fellows, with some now on faculty at Universities in the US and around the world while others have reached leadership positions in the Biotech/Pharma Industry as well as in Start-ups or Venture Capital. Discher and his Lab have coauthored in excess of 200 publications that have garnered more than 30,000 citations and that range in topic from cell and nuclear mechanobiology to self-assembling polymers for cancer drug delivery, with papers appearing in Science, Cell, PNAS, Biophysical Journal, and various Nature journals. Additional Honors and Service include a Presidential Early Career Award for Scientists and Engineers from the US-National Science Foundation, the Friedrich Wilhelm Bessel Award from the Humboldt Foundation of Germany, close to 500 invited talks on six continents, numerous NIH and NSF study sections and review groups, and membership on the Board of Reviewing Editors for Science.