Two important issues that arise in clinical treatment of carcinomas are 1) identification of tumor boundaries to guide surgical resection and 2) identification of biomarkers that accurately predict the invasiveness/aggressiveness of carcinomas in individual patients. The work in this proposal will address both of these issues using ideas that are different from yet complementary to ones currently being explored in cancer biology. Specifically, the PIs will identify the mechanical state of the tumor and use that information to quantify the mechanisms that are responsible for tissue cohesion and boundary maintenance. This will allow them to develop structural order parameters such as cell shape, tissue stiffness, or adhesion molecule expression that better delineate tissue boundaries for future use by pathologists or clinicians. The PIs will also test the conjecture that in combination with their theoretical framework, measurements of tissue fusion experiments or distributions of cell stiffness from primary tumor samples can serve as very accurate mechanical biomarkers for cancer aggressiveness. In addition, the proposed work will broaden participation in the interdisciplinary field of biophysics as the PIs will train a diverse group of undergraduate and graduate students and postdocs, as well as organize conferences and schools that provide professional development opportunities for a large number of young scientists.
Although a physical barrier called the basement membrane initially encapsulates many primary tumors, tumor boundaries are often maintained even when cells break through that barrier. The mechanical and biochemical mechanisms that maintain and regulate these boundaries are poorly understood. Together, the PIs have very recently developed and experimentally verified a theoretical framework that for the first time explains fluid-to-solid transitions in confluent tissues, where there are no gaps between cells. There is mounting evidence that such transitions also occur in cancer tissues. Because fluid-like and solid-like tissues have different mechanisms for migration, self-organization, and cohesion, this proposal will augment and test a theoretical framework for jamming for cancer tissues and investigate how fluid-to-solid transitions affect tumor boundaries. In particular, the PIs will extend their framework to make testable, quantitative predictions for how cancer tissue boundaries evolve in different experimental geometries, and develop new theoretical techniques for predicting how mechanical heterogeneity can lead to rigidity percolation and self-organization of stream-like flows of soft cells. A second new technique will couple tissue models to extra-cellular matrix models to understand how the mechanical properties and motility modes of escaping cells are influenced by the mechanical properties of both the primary tumor and surrounding substrate.
