Wednesday, April 2, 2025
4/2/2025
Nuclear mechanobiology in confined migration - Project Summary The nucleus is the defining feature of eukaryotic cells; it is also the largest and stiffest cell organelle. Increasing evidence suggest that these physical properties of the nucleus can affect diverse cellular functions, and that mechanical forces acting on the nucleus conversely modulate nuclear structure and function, including chromatin organization, gene expression, and genomic integrity. This ‘nuclear mechanobiology’ is particularly relevant in the context of cell migration in 3D in vivo environments, where cells frequently move through tight interstitial spaces that require substantial deformation of the cell nucleus. Examples include cell migration during development, wound healing, inflammation, and cancer metastasis. Our laboratory previously demonstrated that the required deformation of the nucleus limits the ability of cells to migrate through tight spaces, with highly migratory cells often having more deformable nuclei, and that nuclear deformation associated with confined migration can lead to transient nuclear envelope rupture, DNA damage, and changes in chromatin organization. These findings point to an exciting new concept in which the deformation of the nucleus as cells move through tight spaces could activate or suppress transcriptional programs that further enhance migration and modulate other functions, or that could lead to the selection of cells particularly adept at such confined migration. Nonetheless, many questions remain. Over the next five years, we will focus on three complementary and synergistic overarching research areas: (1) investigate how cells generate, apply, and coordinate the large cytoskeletal forces required to move and deform the nucleus through confined spaces; (2) identify the mechanism(s) responsible for confined migration induced changes in chromatin organization, and (3) determine the functional consequences of confined migration on cellular fate and functions, along with the underlying mechanisms. Towards this goal, we have developed several novel experimental platforms that enable extended live-cell imaging of cells migrating through precisely-defined microenvironments while visualizing nuclear deformation, nuclear envelope rupture, DNA damage, and chromatin modifications, and that allow collection of cells after confined migration for subsequent analysis. We will pair these platforms with molecular biology approaches and assays for genome-wide analysis of changes in 3D chromatin organization and gene expression in a range of different cell types, reflecting physiological and pathological scenarios. Our ultimate goal is to uncover general principles in nuclear mechanobiology that will lead to an improved understanding of the impact of migration through tight spaces on cellular function and fate, including the activation or suppression of specific transcriptional programs that may further enhance cell migration or modulate other cellular functions. Insights gained from these studies may help guide therapeutic approach for a variety of clinical conditions, from wound healing and immune-responses to therapies targeting metastatic tumor cells.
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