TTP Labtech, Phenotypic Screening - 15

PHENOTYPIC SCREENING an e-Book Series Cellular Models for Finer Screening

and that basal phosphorylation of EGFR and
cMET was higher in spheroid cultures."
Dr. Ekert suggests that such subtle
microenvironment-induced changes in lung
tumor cell physiology add a level of complexity
to cell-based assays that may be more representative
of the in vivo tumor microenvironment, thereby
improving the predictive capability of screening
assays. He went on to highlight the ability of the
3D system to discriminate between different
EGFR and cMET mutants that inhibited cell
migration and proliferation.
Co-Culture System
While 3D spheroid systems featured heavily
in the talks at the La Jolla meeting, an alternative
approach to developing cell models, the organotypic
3D co-culture platform, was described by Ray
Mattingly, Ph.D., professor of pharmacology at
Wayne State University. "Plexiform neurofibromas
(PNs) are present at birth in up to half of Type 1
neurofibromatosis (NF1) patients," said Dr. Mattingly.
"They grow unpredictably to large sizes, have a
15 | GENengnews.com

significant risk of becoming malignant, and have
poor five-year survival data."
A defining feature of PNs is the number of
different cell types involved (Schwann cells,
fibroblasts, mast cells, and endothelial cells) in which
co-dependent cellular growth pathways are activated.
"Neurofibromin-deficient Schwann cells secrete stem
cell factor that recruits mast cells, which in turn
release growth factors and cytokines that stimulate
the Schwann cells," Dr. Mattingly observed.
Such pathway interactions and feedback loops
are missing in traditional 2D monotypic culture on
plastic dishes, he pointed out. Moreover, the highly
active angiogenic pathways in these cells gives rise to
significant vascularity that can cause complications
during surgery.
"Our goal is to develop the first in vitro
organotypic models of NF1 PNs to allow for
identification of potential therapeutics," commented
Dr. Mattingly. Our guess is that robustly
bioengineered 3D co-culture systems that more
accurately model disease pathways and processes
will allow preclinical drug screening that is much

more representative of likely translational
effectiveness than provided by testing in 2D
monoculture."
Development of the co-culture platform is part
of the Neurofibromatosis Therapeutic Acceleration
Program (NTAP), which is a multi-institutional
effort headquartered at Johns Hopkins.
Chip-Based Platform
The transfected enzyme and metabolism chip,
or TEAMChip, under development by Solidus
Biosciences, is, at its essence, a microarray of
immortalized human cells encapsulated in 3D
matrices. "The TEAMChip accommodates a diverse
array of cells from a variety of tissues, including
primary cells, transformed cell lines, and stem cells,"
said Jonathan Dordick, Ph.D., co-founder and
technical adviser at Solidus and vice president for
research at Rensselaer Polytechnic Institute.
TEAMChip is based upon 3D cell culture, which
employs cells within a physical matrix where the
cells are not bound to a surface substrate but
interact with the matrix components, such as


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TTP Labtech, Phenotypic Screening

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