Collaborative Research: Heterogeneous Cancer Cell Mechanics Differentially Drives Mechanosensing and Migration

University Of California-San Diego, La Jolla CA

Investigators

Abstract

Cancer cells in solid tumors must detach, migrate, and invade surrounding tissues in order to metastasize. This process is regulated by properties of the extracellular matrix, including its stiffness and the its adhesion force with the tumor cells. But tumors are not homogeneous, and these tumor cells can respond differently to their environment. This project will investigate how changes in cellular adhesion properties affect the fate of cells and, in particular, whether they will migrate, proliferate, differentiate, or die -- all key parts of cellular behavior. This project will enhance fundamental understanding of how changes in cellular mechanical properties affect a broad range of cell behaviors. Once this knowledge is expanded, it can be used to influence cellular behavior at the tissue level, which can have a positive impact on understanding process that vary from the pathological (such as cancer growth and metastasis) to the beneficial (such as tissue engineering an regenerative medicine). In addition to the societal impact of the science, the collaborative research team seeks to increase the involvement of underrepresented students in STEM through a 2-pronged approach. First, problem-based learning will be introduced in high school classrooms to expose economically disadvantaged students to research projects and, hopefully, excite them about STEM. Second, leveraging San Diego State University's role as a minority-serving institution and UCSD's background as a highly ranked research university, undergraduate students will be trained in cutting edge, computational and experimental mechanobiology techniques through a multi-institutional instructional and research program. Two research objectives have been established to address the hypothesis that adhesion strength modulates force transduction differently for cells in 2D and 3D environments. First, myosin contractility during directed, 2D migration of tumor cells will be investigated through labile focal adhesions. Second, the force-sensing mechanisms of cancer cells in 3D extracellular matrix will be studied to investigate why there is a difference in tumor cell division and invasion between strongly and weakly adherent cells. In order to investigate these aims, a microfluidic system will be used that can separate well-characterized epithelial cancer cell lines by their adhesive properties. Three types of endothelial cancer cells will be investigated (lung, prostate, and mammary) to insure that the force-sensing mechanisms are consistent across the tumor types. Traction-force microscopy will be employed to study the molecular and cellular-level mechanics. Cells will also be treated with function-blocking or function-enhancing antibodies that will weaken or strengthen the adhesion strength, respectively. The experimental studies will be combined with computational modeling in order to clearly elucidate the underlying mechanisms of the observed behavior. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.