Cell mechanoresponses in physiologically relevant microenvironments - Summary: Cell migration is a fundamental cellular phenomenon that plays a pivotal role in (patho)physiological events, including organ development, tissue regeneration and cancer metastasis. Our long-term goal is to achieve a comprehensive understanding of the mechanisms of cell migration in order to develop novel therapeutic tools and strategies to prevent the initiation and progression of diseases, including cardiovascular pathologies, aging, and cancer. Building on the PI's postdoctoral work, the lab explores how the physical cues of the local microenvironment (e.g., confinement, viscoelasticity, stiffness, pressure and shear stress) convert into biochemical signals to influence the migratory behavior of cells. Over the next five years, we will employ state-of-the-art microfabricated devices, materials, optogenetic tools, single-cell transcriptomics and computational simulations to elucidate the effects of pressure forces on cell migration and viability. The scientific premise of this application is based on prior studies showing that cells experience elevated pressure forces during various stages of migration and invasion, including extra/intravasation and interstitial migration. Although the widely held view is that cells can adapt to mechanical cues, an open and unaddressed question is how elevated pressure affects cell behavior in diverse, yet physiologically relevant, microenvironments. To answer this question, we will investigate the interplay between pressure forces and different microenvironmental cues (physical or biochemical) in the regulation of cell migration. We will also assess whether long-term cell exposure to high pressures alters the sensitivity of cell motility to physical cues. Last but not least, we will dissect the relative roles and potential crosstalk between confinement and pressure in cell death regulation. Taken together, the proposed studies, which are supported by highly encouraging preliminary results, will delineate the underlying mechanisms regulating cell behavior in physiological environments and generate novel conceptual information that will facilitate the identification of new therapeutic targets aimed at promoting or preventing cell motility in vivo.
