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Region(s) of Interest: United Kingdom
Institution(s): King’s College London
How cell nuclei squeeze into tight spaces
As cells move throughout our bodies, they often have to squeeze
through tight nooks and crannies in their environment, reliably
springing back to their original shape. The structures involved in this
process are still a mystery, but in a study published August
22 in Developmental Cell, a research team reports one protein
responsible for giving a cell's nucleus its durable, deformable nature.
These results, the authors say, may explain the invasiveness of certain
cancer cells.
"The nucleus is the fattest organelle in the whole cell, and really needs to be squished if a cancer cell wants
to metastasize throughout the body," says Maddy Parsons, Professor of Cell Biology at King's College
London, whose research group led the study. "There's a really complex network of proteins that keeps the
cell from buckling in on itself when it's faced with a tight squeeze."
The researchers pinpointed one protein responsible--fascin--that is known to be at unusually high levels in
cancer cells. Originally, says Parsons, fascin was only thought to exist at the cell's edge as a "bundling
protein," where it binds and stabilizes spiky finger-like protrusions called filopodia at the cell's plasma
membrane. These structures allow the cell to sense its surrounding environment and pull itself through
tissue. Now, the researchers have found that fascin also sits at the periphery of the nuclear envelope (the
membrane that surrounds the nucleus), binding to different structures there to add stability and prevent
collapse.
"All cells have a cytoskeleton made from lots of filaments of a protein called actin that give the cell its
architecture, but without other proteins added on, the skeleton will buckle under stress," says Parsons.
"Proteins like fascin that bind onto this cytoskeleton add an element of stability and flexibility--it makes
the cell more mechanically stable and able to rapidly respond to the environment to change shape. This
data we have, showing fascin at the nuclear periphery, has opened up a new way of thinking about how
this protein controls cancer cell movement."
To investigate how fascin controls cancer cell migration, Parsons and her team in one set of experiments
placed human cancer cells into a series of artificial microchannels, which are small devices with pore sizes
ranging from large pores that a cell can easily maneuver through to spaces as small as 2 microns wide, into
which the cell can barely fit. By reducing intercellular levels of the fascin protein, they found that the cells
were unable to squish their nuclei enough to fit into small channels. This suggests that cancer cells may use
fascin to better navigate through different densities of tissues that they face during their invasion away
from a solid tumor.
"I think what we're showing is that fascin has more than one important role in controlling cancer cell
metastasis," Parsons adds. "Importantly, this is also revealing new ways that we can target fascin to block
its function in cancer cells."
Parsons and her team are still eager to determine the forces controlling fascin in cancer cells. "We're really
still in the dark about what proteins are controlling these different functions of fascin," she says. "We still
don't know what proteins and signals are telling fascin to move from the cell's edge to the nucleus, so these
are the next questions we hope to tackle."
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The authors were funded by the Medical Research Council, the Royal Society, and the Wellcome Trust.
Developmental Cell, Jayo et al.: "Fascin regulates nuclear movement and deformation in migrating
cells," http://www.cell.com/developmental-cell/fulltext/S1534-5807(16)30514-7.
DOI: http://dx.doi.org/10.1016/j.devcel.2016.07.021
Related Files
Video 1:
This is a time-lapse microscopy movie of human breast cancer cells migrating into channels of different
widths (20um, 10um and 5um). The far left panel show scells moving easily into channels that are 20um
wide. The central panel shows that cells take longer to migrate into the smaller 10um size channels. The
far right panel shows cells are unable to migrate into 5um wide panels and protrude their cytoplasm into
the channel, but the nuclei remain outside the channel. This indicates that the size and deformability of the
cell nuclei acts as a limiting factor for cells to squeeze into small spaces. (Credit: Jayo et al.)
Video 2:
This is a fluorescent time-lapse movie of the actin cytoskeleton in fibroblast cells. Cells in the right panel
are expressing the actin-binding protein fascin, cells in the left panel have been depleted of fascin using
shRNA. Movies show that cells that express fascin use the actin cytoskeleton to move their nuclei
backwards during migration to allow the cells to move forward, and that this does not occur when fascin is
removed from cells. This shows that fascin is important in controlling the movement of the cell nucleus
and this contributes to the ability of cells to migrate. (Credit: Jayo et al.)
Author Contact:
Maddy Parsons
Professor, Randall Division of Cell & Molecular Biophysics
King's College London
+011 44 (207)-848-8164
[email protected]
Media Contact:
Jenny Gimpel
Public Relations Manager (Health)
+011 44 (207)-848-4334
[email protected]