Advances in personalized
medicine allow doctors to select the most promising drugs for certain types of
malignant tumors. But what if before initiating treatment, they could go a step
further and use a mini-model of the human body to see how each patient’s actual
tumor responds to the drugs and learn if and where the tumor is likely to
That’s the idea behind a new invention by scientists at Wake
Forest Baptist Medical Center’s Institute for Regenerative Medicine. In the
journal Biotechnology Bioengineering, the team reports on its “metastasis-on-a-chip”
system believed to be one of the first laboratory models of cancer spreading
from one 3D tissue to another.
The research team is working to further develop the system in
hopes that it can one day be used to quickly reveal the best way to treat an
individual patient’s cancer.
“We believe the metastasis-on-a-chip system has potential for
making meaningful advances in cancer investigation and drug discovery,” said
Aleks Skardal, Ph.D., lead author and an assistant professor of regenerative
The current version of the system models a colorectal tumor spreading
from the colon to the liver, the most common site of metastasis. Skardal said
future versions could include additional organs, such as the lung and bone
marrow, which are also potential sites of metastasis. The team also plans to
model other types of cancer, such as the deadly brain tumor glioblastoma
To create the system, researchers encapsulated human intestine and
colorectal cancer cells inside a biocompatible gel-like material to make a
mini-organ. A mini-liver composed of human liver cells was made in the same
way. These organoids were placed in a “chip” system made up of a set of
micro-channels and chambers etched into the chip’s surface to mimic a
simplified version of the body’s circulatory system. The tumor cells were tagged
with fluorescent molecules so their activity could be viewed under a microscope.
To test whether the system could model metastasis, the researchers
first used highly aggressive cancer cells in the colon organoid. Under the
microscope, they saw the tumor grow in the colon organoid until the cells broke
free, entered the circulatory system and then invaded the liver tissue, where another
tumor formed and grew. When a less aggressive form of colon cancer was used in
the system, the tumor did not metastasize, but continued to grow in the colon.
To test the system’s potential for screening drugs, the team
introduced Marimastat®, a drug used to inhibit metastasis in human
patients, into the system and found that it significantly prevented the
migration of metastatic cells over a 10-day period. Likewise, the team also
tested 5-fluorouracil, a common colorectal cancer drug, which reduced the
metabolic activity of the tumor cells.
“We are currently exploring whether other established anti-cancer
drugs have the same effects in the system as they do in patients,” said
Skardal. “If this link can be validated and expanded, we believe the system can
be used to screen drug candidates for patients as a tool in personalized
medicine. If we can create the same model systems, only with tumor cells from
an actual patient, then we believe we can use this platform to determine the
best therapy for any individual patient.”
The system also gives scientists the opportunity to study the microenvironment,
or environment in which the tumor exists. This is a relatively new focus of
cancer research. For example, the scientists learned that a “stiffer” tumor was
more apt to metastasize, suggesting the possibility of using drugs to alter the
mechanical properties of a tumor to reduce its likelihood of spreading.
The system has the potential to address some of the shortcomings
of current research methods. For example, the results from traditional 2D
studies in laboratory dishes as well as studies in animals often are not
applicable to human patients. Often, seemingly promising drug candidates may fail
when they reach studies in humans.
scientists are currently working to refine their system. They plan to use 3D
printing to create organoids more similar in function to natural organs. And they
aim to make the process of metastasis more realistic. When cancer spreads in
the human body, the tumor cells must break through blood vessels to enter the
blood steam and reach other organs. The scientists plan to add a barrier of
endothelial cells, the cells that line blood vessels, to the model.
are trying to make it as realistic as we can,” said Skardal.
concept of modeling the body’s processes on a miniature level is made possible because
of advances in micro-tissue engineering and micro-fluidics technologies. It is
similar to advances in the electronics industry made possible by miniaturizing
electronics on a chip.
research was supported by the Golfers Against Cancer, the Comprehensive Cancer
Center at Wake Forest Baptist, and the Wake Forest Institute for Regenerative
Medicine Promoting Discoveries Award.
Skardal, Ph.D., lead author, has filed a patent application using the
metastasis-on-a-chip for modeling cancer metastasis in the lab.”
are: Mahesh Devarasetty, B.S., Steven Forsythe, B.S., Anthony Atala, M.D., and
Shay Soker, Ph.D., of Wake Forest Baptist.