Using a microengineered device that acts as an obstacle course
for cells, researchers have shed new light on a cellular metamorphosis
thought to play a role in tumor cell invasion throughout the body.
The epithelial-mesenchymal transition (EMT) is a process in which
epithelial cells, which tend to stick together within a tissue, change
into mesenchymal cells, which can disperse and migrate individually. EMT
is a beneficial process in developing embryos, allowing cells to travel
throughout the embryo and establish specialized tissues. But recently
it has been suggested that EMT might also play a role in cancer metastasis, allowing cancer cells to escape from tumor masses and colonize distant organs.
For this study, published in the journal Nature Materials, the
researchers were able to image cancer cells that had undergone EMT as
they migrated across a device that mimics the tissue surrounding a
tumor.
"People are really interested in how EMT works and how it might be
associated with tumor spread, but nobody has been able to see how it
happens," said lead author Ian Y. Wong, assistant professor in the Brown
School of Engineering and the Center for Biomedical Engineering, who
performed the research as a postdoctoral fellow at Massachusetts General
Hospital. "We've been able to image these cells in a biomimetic system
and carefully measure how they move."
The experiments showed that the cells displayed two modes of motion. A
majority plod along together in a collectively advancing group, while a
few cells break off from the front, covering larger distances more
quickly.
"In the context of cell migration, EMT upgrades cancer cells from an
economy model to a fast sports car," Wong said. "Our technology enabled
us to track the motion of thousands of 'cars' simultaneously, revealing
that many sports cars get stuck in traffic jams with the economy cars,
but that some sports cars break out of traffic and make their way
aggressively to distant locations."
Armed with an understanding of how EMT cancer cells migrate, the
researchers hope they can use this same device for preliminary testing
of drugs aimed at inhibiting that migration. The work is part of a
larger effort to understand the underpinnings of cancer metastasis,
which is responsible for nine out of 10 cancer-related deaths.
'Obstacle course for cells'
To get this new view of how cancer cells move, the researchers
borrowed microelectronics processing techniques to pattern miniaturized
features on silicon wafers, which were then replicated in a rubber-like
plastic called PDMS. The device consists of a small plate, about a
half-millimeter square, covered in an array of microscopic pillars. The
pillars, each about 10 micrometers in diameter and spaced about 10
micrometers apart, leave just enough space for the cells to weave their
way through. Using microscopes and time-lapse photography, the
researchers can watch cells as they travel across the plate.
"It's basically an obstacle course for cells," Wong said. "We can
track individual cells, and because the size and spacing of these
pillars is highly controlled, we can start to do statistical analysis
and categorize these cells based on how they move."
For their experiments, the researchers started with a line of benign
cancer cells that were epithelial, as identified by specific proteins
they express. They then applied a chemical that induced the cells to
become malignant and mesenchymal. The transition was confirmed by
looking for proteins associated with the mesenchymal cell type. Once all
the cells had converted, they were set free on the obstacle course.
The study showed that about 84 percent of the cells stayed together
and slowly advanced across the plate. The other 16 percent sped off the
front and quickly made it all the way across the device. To the
researchers' surprise, they found that the cells that stayed with the
group started to once again express the epithelial proteins, indicating
that they had reverted back to the epithelial cell type.
"That was a remarkable result," Wong said. "Based on these results,
an interesting therapeutic strategy might be to develop drugs that
downgrade mesenchymal sports cars back to epithelial economy models in
order to keep them stuck in traffic, rather than aggressively invading
surrounding tissues."
As for the technology that made these findings possible, the
researchers are hopeful that it can be used for further research and
drug testing.
"We envision that this technology will be widely applicable for
preclinical testing of anti-migration drugs against many different
cancer cell lines or patient samples," Wong said.
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