Princeton University physical scientists will partner with researchers at four other institutions to explore the driving forces behind the evolution of cancer under a five-year, $15.2 million award from the National Cancer Institute.
The Princeton Physical Sciences-Oncology Center was launched Oct. 26 as one of 12 centers in the institute's new network of Physical Sciences-Oncology Centers. Collaborating with Princeton will be: the University of California-San Francisco; the Johns Hopkins Hospital; the University of California-Santa Cruz; and the Salk Institute for Biological Studies in La Jolla, Calif.
The center's goal is to understand the explosive evolution of cancer under stress at a deep theoretical and experimental level by leveraging the strengths of an interdisciplinary team of physicists, engineers, chemists, biochemists and oncologists. Using a physics-based approach, the team intends to better grasp the rules or laws that govern how cancer evolves, which may one day inform entirely new treatment approaches.
"The mortality rates for many cancers are flat to rising," said Robert Austin, the center's principal investigator and a Princeton professor of physics. "It's true that people are living longer than they used to live, but in the end, the cancer wins most of the time. Our current 'shock and awe' approach to treatment may not be the best thing to do -- we're leaving behind small populations of highly resistant cells."
This course may, in turn, contribute to the development of intractable cancer recurrences. Because it is nearly impossible to kill every single cancerous cell in the body, those that survive the stress of chemotherapy and radiation often have undergone mutations that render them resistant to traditional treatments, capable of rapid reproduction and therefore exceedingly dangerous.
"The evolution of cancer is the Achilles' heel of cancer treatment," said Thea Tlsty, the center's co-principal investigator and professor of pathology at the University of California-San Francisco. "It's why we can't deal with metastasis or drug resistance; it's the thing that kills people. We're addressing these important questions -- how does evolution lead to metastasis and resistance, and how can we use evolution to skew the outcome in a different way?"
Research in the center hinges on the use of microfabrication techniques to create complex habitats that provide an unprecedented ability to manipulate many variables at once and observe how cells respond, allowing the team to determine how different conditions promote or inhibit rapid cancer evolution and tumor formation.
The results they obtain will inform the development of sophisticated computer models that simulate tumor growth and predict how and when certain tumors might invade surrounding tissue. Data obtained from these simulations will, in turn, suggest new questions to ask and explore.
"One ambitious goal is the creation of an 'in silico' growing tumor, meaning a realistic model on the computer, which could suggest new experiments, test new hypotheses, predict behavior in experimentally unobservable situations, and be employed for early detection," said team member Salvatore Torquato, a professor in the Department of Chemistry, the Princeton Institute for the Science and Technology of Materials, and the Princeton Center for Theoretical Science. "As you go back and forth to refine the experiments and the theoretical models, you're coming to a real understanding of cancer. And that is what we'd ultimately like to do."
The experimental microhabitats, being developed jointly between the labs of Austin and James Sturm, a professor of electrical engineering and the director of the Princeton Institute for the Science and Technology of Materials, are constructed on chips of silicon or polydimethylsiloxane (PDMS), a silicon-based plastic. Featuring a series of wells just 10 to 100 microns in size (a human hair is roughly 100 microns in diameter), the devices allow for the growth of distinct but interconnected populations of cells. Ultrasmall channels link the compartments together, providing avenues for cells in different communities to move and interact with one another. A given chip might contain tens to hundreds of interconnected wells, each capable of housing hundreds of cells.
A series of pumps and valves on the chips will enable the delivery of a variety of mechanical and chemical stressors, such as extreme pressure or chemotherapeutic agents, to different populations of cells living under a range of different conditions, including gradients of temperature and resource availability.
"A tumor is a heterogeneous thing with many different metapopulations of cells inside it," Austin said. "We're trying to represent the biological environment of a tumor and hopefully understand the rules by which a tumor evolves."