Models of collective migration that integrate single-cell polarity and mechanics

Project Summary/Abstract
Collective cell migration is critical in wound healing, morphogenesis, gastrulation, as well as in pathological
processes. This collective motion arises from coordination of the biochemical polarization of individual cells.
Some of the biological details of this coordination have been identified – many different cell types integrate
information from cell-cell contact through cadherins in order to repolarize Rho GTPase activity. These biochemical
events drive stereotyped reactions like contact inhibition of locomotion (CIL), where cells repolarize and crawl
away from contact. There is a critical gap in our understanding between identifying molecular players in cell-
cell interactions and being able to predict how changes in cell-cell interactions drive collective migration of an
epithelial layer or an invading stream of cells. A long-term goal of the Camley group is developing computational
physical models of collective cell migration to bridge this gap. This project addresses that goal by building models
of collective cell migration with realistic geometry, mechanics and cell-cell signaling to study:
1. Determining the effect of cell geometry on cell-cell interactions like contact inhibition of locomotion
Assays to test cell-cell interactions in collisions of migrating cells are performed on two-dimensional substrates,
allowing collisions to occur between cells with broad lamellipodia. However, in vivo, cell-cell interactions occur in
a context established by three-dimensional extracellular matrix, mechanical confinement, and neighboring cells,
which are all known to alter motility. How can cells reliably integrate cell-cell contacts with highly variable
contact areas and durations to coordinate their motion? We will develop models to describe the effect of
cell and matrix geometry on cell-cell collisions. This will include recent experiments on cell-cell collisions on
suspended fibers, in which our collaborators found traditional contact inhibition of locomotion is near-absent.
2. Understanding how myosin activity fluctuations and mechanotransduction regulate cell-cell rupture events
Invasion of cells in both normal and diseased tissue can occur by cells breaking off from a larger group. This is a
key part of collective invasion. What controls the critical step of cell-cell rupture? We hypothesize that these
rare events are dependent on fluctuations in the level of motor proteins like myosin at cell-cell junctions. We will
develop models to describe this strand invasion, how dissemination depends on cell motility, and the ability of
cells to sense the forces exerted on junctions. We will develop tools to infer models of feedbacks between the
tension at the cell-cell junction and cell motility directly from experimental data. These will be used on data from
collaborators studying invasion in controlled microfluidic geometries. In addition, we will develop models studying
how the size of clusters breaking from a strand depend on the strand geometry.
Together, these models provide links from physical and molecular aspects of cell-cell collisions to large-scale
collective migration, and will drive future questions in collective migration and development.

Grant Number: 5R35GM142847-05
NIH Institute/Center: NIH
Principal Investigator: Brian Camley