When a cell needs to migrate through small spaces, it needs to change its shape to fit through the opening. During this process, deformation of the nucleus represents a critical challenge, since the nucleus is the largest and stiffest part of a cell. A softer nucleus is expected to make this movement through small spaces easier, because it would allow the cell to deform to a greater extent. However, the behavior of known factors that regulate changes in the stiffness of the nucleus is inconsistent with this simple scenario and suggests a more complex situation that is not yet understood. This project aims to fill this knowledge gap by probing nuclear mechanics during cellular migration, including through small spaces, using a novel mechanical testing technique. This technique does not require contact with the cell nor the use of external labels. Thus, it can be used to probe the nucleus of migrating cells, which are not physically accessible. The knowledge gained from this project will support advancements in understanding of how cancer cells invade healthy tissue and metastasize. This interdisciplinary project will also provide an opportunity to implement hands-on educational courses for undergraduate engineering students to design and build advanced photonic instrumentation for biomedical applications.
Cell migration in confined microenvironments is central to many processes, such as tissue development and immune cell trafficking, and, represents a critical challenge for metastatic spreading. This project will enable direct measurements of dynamic changes in nuclear mechanical properties during confined cell migration using Brillouin microscopy. The validated technique will be used measure nuclear modulus modulation and its intracellular regulators, first in response to physical cues of the microenvironment and then during migration through a confined microenvironment. Thus, this research will unveil the mechanical properties of the nucleus that are advantageous for migration through small constrictions; specifically, it will identify nuclear properties that are critical within the metastatic cascade and characterize how they evolve during metastatic progression. The improved fundamental knowledge gained with this project may ultimately lead to new diagnostic and therapeutic targets for metastasis based on phenotyping of nuclear mechanics.
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.
