3D model reveals secrets of metastasis
CAMBRIDGE, Mass. (July 10, 2006) — A cancer cell
breaks away from a primary tumor and settles in a new
location, where it once again divides. Pharmaceutical
companies typically use simplistic two-dimensional assays
for this process, which is known as metastasis, to evaluate
anti-cancer therapeutics. In these assays, cells crawl
across the surface of a matrix, traveling in a single
plane. But a new study indicates that this approach
misses some crucial phenomena.
Working in the labs of Whitehead Member Paul
Matsudaira and MIT professor Douglas Lauffenburger,
postdoctoral researcher Muhammad Zaman discovered that
cells move quite differently in three dimensions. His
study, which focused on human prostate tumor cells,
appeared this week in the online early edition of Proceedings
of the National Academy of Sciences.
“Our findings help explain why two-dimensional
assays for metastasis-inhibiting drugs do not
effectively predict their effects in tissue,”
says Douglas Lauffenburger, who is director of
MIT’s Biological Engineering Division. |
“Two-dimensional assays ignore the obstacles
that cells face in their natural contexts,” explains
Zaman, who recently became an assistant professor at
the University of Texas at Austin. “In 3D, cells
move through a thick jungle of fibers, or ‘vines’,
that hinder forward progress.”
Cells must either squeeze through or chop up these putative
vines to get anywhere. As a result, they move slower
in three dimensions.
In an interesting twist, all cells need at least some
vines to move, as they latch onto the “branches”
with claw-like proteins called integrins and pull themselves
forward. When Zaman disabled some of these claws, in
a manner analogous to certain anti-cancer drugs, the
cells moving across the top of the jungle canopy (in
two dimensions) needed a greater number of vines to
keep up their pace, while cells plowing through the
jungle instead needed vines chopped to maintain the
same speed. The complexity of this situation is further
increased in that the cells become dramatically sensitive
to the stiffness of the vines when the integrins are
disabled and consequently tend to squeeze through the
vines rather than pushing them aside.
“Our findings help explain why two-dimensional
assays for metastasis-inhibiting drugs do not effectively
predict their effects in tissue,” says Lauffenburger,
who is director of MIT’s Biological Engineering
Division. He believes pharmaceutical companies will
eventually use three-dimensional assays, accompanied
by appropriate computational models such as that also
recently published by Zaman (in Biophysical Journal
in 2005), to determine how drugs affect metastasis.
But technology must improve before more complicated
3D studies are attempted. For his 3D work Zaman worked
with one sample at a time, using a special confocal
microscope at the Whitehead-MIT BioImaging Center. The
microscope divided each specimen into virtual slices,
generating a new stack of images every 15 minutes.
“It took me about a year to get enough data because
the microscope wasn’t designed for high-throughput
experiments,” he says. Fortunately, the BioImaging
Center has one of the most powerful sets of computers
at MIT and the imaging processing and analysis went
quite quickly.
“Muhammad was successful for two reasons,”
says Matsudaira. “His computational model predicted
what would happen in virtual experiments and then he
was able to go straight to test the predictions with
these complicated 3D experiments. As a result, the sophisticated
models of cell movement enhance our understanding of
key biological processes, including metastasis.”
The research was funded by the National Institutes of
Health, the National Science Foundation and the Sokol
Foundation for Cancer Research.
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