Investigators at a new University of Pennsylvania research center will focus on key physical principles that underpin cancer’s development and growth.

A five-year, $10 million grant award from the National Institutes of Health is supporting the establishment of the Physical Sciences Oncology Center at Penn, or PSOC@Penn. It is one of four centers the National Cancer Institute of the NIH is funding across the country as part of its Physical Sciences in Oncology Network. The network was started in 2009 in recognition of the fact that perspectives rooted in physics, mathematics, chemistry and engineering can all contribute to cancer research.

The Penn team members will make fundamental physical measurements as they clarify mechanisms of how tumors become palpably distinct masses and also how such physical changes contribute to tumor growth. Their research will focus on liver cancer; more than 30,000 people in the United States are diagnosed each year with 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 needed.

“A key challenge facing cancer research in this age of precision medicine is to deeply comprehend the molecular causes and consequences of tissue changes that are often first measured by clinicians in physical exams of tumors,” said center leader Dennis E. Discher, the Robert D. Bent Professor in the School of Engineering and Applied Science.

The Center represents a convergence of interests and accomplishments of co-investigators, including professors Rebecca Wells (Medicine), Paul Janmey (Physiology), Emma Furth (Pathology), David Kaplan (Gastroenterology & Immunology), Roger Greenberg (Cancer Biology) and Mark Lemmon (Biochemistry) in Penn’s Perelman School of Medicine; Ravi Radhakrishnan (Bioengineering), Vivek Shenoy (Materials Science and Engineering) and John Crocker (Chemical and Biomolecular Engineering) in Penn’s School of Engineering and Applied Science; and Andrea Liu (Physics & Astronomy),  Tobias Baumgart (Chemistry) and Wei Guo (Biology)in Penn’s School of Arts & Sciences.

“Many tumors are first detected as hard lumps of stiff tissue,” Wells said. “In some cases such as breast cancer, increased tissue stiffness appears to be a risk factor for cancer. Our research will 
focus on liver cancer because current clinical evidence suggests that liver stiffening may work in the same way, as a high risk factor for developing that disease.”

The researchers will interact closely, bringing together world leaders in cell and tissue mechanobiology and physics-based theory. They will also employ single molecule imaging and molecular biophysics in foundational studies of molecular and tissue profiles, which are rapidly emerging as a way to precisely define a patient’s disease.

“Results from our initial studies already suggest that stiffening of tissue can increase cell proliferation and lead to other cellular changes that contribute to cancer,” said Janmey.

Specific molecules and cells that Center investigators discover to be contributors to physical changes in liver cancer will become candidates for new therapies.

The key scientific issue driving PSOC@Penn’s research agenda is an emerging awareness that tumor microenvironments can contribute to how cell sub-populations are selected to grow and further evolve. In solid tumors such as liver cancer, it has long been known that stiff, scar-like collagen accumulates 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 proliferation and can influence gene expression related to cancer’s spread.

“We hypothesize that differences between cells in a given population can arise due to physical properties of microenvironments,” Discher said. "Furthermore, mutations might also be caused directly by physical properties of microenvironments and thus drive cancer."

PSOC@Penn will approach questions regarding the effects of physical microenvironment on tumor development with new multi-disciplinary methods. While focused on liver cancer, the Center will develop widely applicable techniques for measuring both the mechanical properties and molecular makeup of a patient’s tumors compared to adjacent normal tissue. Theoretical approaches from the fields of soft matter physics and engineering will enable better interpretation of clinical results and predict effects of physical, biochemical and drug interactions.

Physicochemical studies of single cancer cells will go beyond the cell membrane and into the nucleus. 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. Center researchers will visualize this process 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 these molecules’ functions.  

The Center also aims to understand how the shape of the cell’s nucleus changes as part of a response to altered microenvironments. Nuclei differ in their stiffness, which can prevent them from moving through tight tissue spaces. Whether and why such processes might also lead to damage of the DNA contained therein will be important to quantify, as DNA damage is a likely cause of mutations that drive cancer. Similar studies will be conducted of the nucleus in other types of liver cells, including immune cells that might also be made to attack cancer cells. New biophysical concepts, as well as methods, tools and mathematical theories, are all integral to the diversity of the Center’s efforts.

"Integration across the Penn campus will be enhanced by the new Center’s connections to other centers in the Physical Sciences in Oncology Network," Discher said. "This should stimulate the pace of discovery in these exciting topics."

This highly interdisciplinary effort will extend beyond Penn’s campus and the NIH’s network. Education and outreach activities will build bridges between communities. The Center will promote dialogue between physical scientists and theorists on the one side, and cancer biologists on the other, in order to facilitate the development of new breakthroughs. Seminars, symposia, and additional Center activities will be open to all interested researchers as well as the public, and outreach will extend to demonstrations at cancer awareness forums. Penn’s new Center will support the cancer research community by providing opportunities for quantitative investigators and for students to receive education in cancer biology and to become embedded in laboratories. The Center will also support pilot grants for interdisciplinary, collaborative research at the intersection of the physical sciences and cancer research.

Key collaborators of the Center include Chi Van Dang, director of Penn’s Abramson Cancer Center; liver and transplant surgeons Kim Olthoff and Abraham Shaked; cell biologist Michael Lampson; and outreach coordinator James McGonigle.