Cell-Matrix Memory and Remodeling in Cross-Environment Cell Invasion

This award will study how living cells move across dissimilar physical environments. Cells can sense and respond to their current surrounding environment. However, it is currently unclear whether cells remember the physical properties of their prior environment, and whether this mechanical memory dictates how they move through new environments.

This gap in knowledge prevents understanding of whether cells that leave tumors or diseased tissues continue to retain those mechanical memories. The objective of this research is to integrate experiments and computational modeling that combines two mechanically different environments through which cells migrate. This project will reveal how forces generated by cells modify their surroundings, and how the memory of these modifications regulates cell movement through new environments.

Better understanding of cells and their mechanical memory could enable more effective therapies for cancer and fibrosis that account for both the current and past physical environment of cells. This research project combines methodologies from mechanical engineering, biomaterials, physics-based modeling, and cell biology. This project will train graduate students in multidisciplinary research, provide training and education opportunities to undergraduate students, and disseminate scientific findings to broader society through outreach activities.

Cells adopt different modes of mechano-sensing and migration through environments of varying mechanics – e.g., fast motility on stiff surfaces, amoeboid squeezing through confinement, and force-based mesenchymal migration through fibrous collagen. In addition, it has been shown in stem cells that cell fate can be reprogrammed using a stored mechanical memory of past environments.

However, in these studies, elastic hydrogels are passive providers of mechanical cues. In contrast, fibrous collagen matrices can undergo active remodeling. Because memory-laden cells remain mechano-activated even after leaving their priming environment, this project investigates whether high forces of stiff-primed cells result in greater collagen remodeling, thus encoding a ‘matrix memory’ for follower cells to exploit for invasion.

These questions are addressed through spatiotemporal invasion measurements of primed cells implanted in collagen and in silico modeling with a systems-based model for memory regulation combined with a lattice-based framework for cell invasion. Such findings would generate new knowledge in a variety of biological contexts – from tumor invasion, wound healing, regeneration, and development – in which cells move across environments.

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.