# Nuclear mechanobiology in confined migration

> **NIH NIH R01** · CORNELL UNIVERSITY · 2021 · $314,168

## Abstract

Project Summary
Cell migration is essential for numerous physiological processes, including development, tissue homeostasis,
and wound healing. At the same time, cell migration enables tumor cells to invade other tissues, enter/exit the
circulation, and spread to distant sites in the body to form metastases. While these facts have motivated research
on cell migration for many decades, one aspect that has only recently received attention is the physical challenge
that cells face during migration in three-dimensional (3D) environments, and the resulting impact on cellular
structure and function. In tissues, cells frequently move through tight spaces that require substantial deformation
of the cell nucleus, which is the largest and stiffest organelle. The associated mechanical stress can result in
nuclear envelope rupture, DNA damage, and changes in genomic organization. Many questions, however,
remain, including the underlying molecular mechanisms, the functional consequences, and the variability across
different cell lines. The central goal of this proposal is to identify the characteristic changes in chromatin
organization associated with confined migration, determine the molecular mechanisms responsible for
the mechanically-induced changes in chromatin organization and DNA damage, and assess the
functional consequences of these events. To achieve this goal, we have developed 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.
These platforms will be paired with molecular biology approaches and assays for genome-wide analysis of
changes in 3D chromatin organization and gene expression in a panel of well-characterized cell lines
representing both tumorigenic and non-tumorigenic cells. In the first aim, we will identify migration-induced
changes in chromatin organization and gene expression, determine the molecular mechanisms responsible for
altered chromatin organization, and assess the functional consequences of the altered chromatin organization.
In the second aim, we will identify the molecular mechanisms for DNA damage during confined migration and
determine the impact of migration-induced DNA damage on cell viability, cell cycle progression, and senescence.
We will focus our studies on the earliest events resulting from altered chromatin organization and DNA damage,
which we expect to exhibit less variation across multiple cell types than longer-term effects. 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 genomic stability, 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 he...

## Key facts

- **NIH application ID:** 10136048
- **Project number:** 5R01GM137605-02
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Jan Lammerding
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $314,168
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136048

## Citation

> US National Institutes of Health, RePORTER application 10136048, Nuclear mechanobiology in confined migration (5R01GM137605-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10136048. Licensed CC0.

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