Credit: L. Francisco Lorenzo-Martín (EPFL)
In a
breakthrough for cancer research, scientists at EPFL have created lab-grown
mini-colons that can accurately mimic the development of colorectal tumors,
offering a powerful new tool for studying and testing treatments for the
disease.
As our battle against cancer rages on, the quest for
more sophisticated and realistic models to study tumor development has never
been more critical. Until now, research has relied on animal models and
simplified cell culture methods, which are valuable but cannot fully capture
the complex interplay of factors involved in tumor development.
Even newer, more advanced models for studying cancer,
such as organoids—tiny, lab-grown versions of organs—do not faithfully
replicate the cell behaviors and tissue architectures seen in actual tumors.
This gap has significantly hindered our understanding
of the intricate processes underlying cancer initiation, progression, and
response to treatment, and calls for more sophisticated models to accurately
mimic the disease's complexity.
In a significant leap forward for cancer modeling, scientists have combined microfabrication and tissue engineering techniques to develop miniature colon tissues that can simulate the complex process of tumorigenesis outside the body with high fidelity, giving rise to tumors that closely resemble those found in vivo.
38-hour time-lapse video of tumor development in
a mini-colon 9 days after oncogenic recombination. Credit: L. Francisco
Lorenzo-Martín (EPFL)
The breakthrough, published in Nature, was
made by Luis Francisco Lorenzo Martín, Tania Hübscher and other members of the
group of Matthias Lütolf at EPFL, with input from the group of Freddy Radtke
(EPFL) and colleagues at Roche's Institute of Human Biology.
The mini-colons are topobiologically complex, meaning that they not only
replicate the physical structure of colon tissue, including its distinctive
crypt-and-lumen architecture, but they also mimic the cellular diversity
present in the actual colon tissue during healthy and diseased states.
Optogenetics: Turning cancer 'on'
Another important feature of the mini-colons is that they can be induced to
develop tumors "at will" and in targeted areas—a massive advantage
for cancer research. The researchers were able to turn inducible
oncogenic genes on using "optogenetics." This cutting-edge technique
uses light to control biological processes such as gene expression.
By integrating a blue-light-responsive system into the mini-colons, the
researchers made them undergo controlled oncogenic mutations, which can reveal
tumor evolution with unprecedented details. This optogenetic approach allowed
the scientists to induce targeted changes in specific cell populations within
the mini-colons, mimicking the localized onset of colorectal cancer in the
body.
"In essence, we used light to trigger tumorigenesis by turning on
oncogenic driver mutations in a spatiotemporally controlled manner in healthy
bioengineered colon epithelial organoids," says Lütolf, who is also the
founding director of Roche's new Institute of Human Biology.
"This basically allows you to watch tumor formation in real-time and
do very detailed analyses of a process that's very difficult to study in a
mouse."
The ability to trigger these genetic changes with light in the miniature colons not only
allows more controlled and more precise activation of the oncogenes, but also
provides a powerful tool to study the dynamic processes of tumor development and the cellular response to these mutations
in real-time. This innovative use of optogenetics opens up new
possibilities for dissecting the molecular and cellular mechanisms of cancer.
By manipulating genetic and environmental conditions, the
researchers were also able to replicate and observe a range of tumor behaviors
in the mini-colons, and even identified key factors influencing cancer
progression—for example, the protein GPX2, which associated with stem cell
characteristics and tumor growth.
This research offers a potent new tool for exploring the underlying mechanisms of colorectal cancer and testing potential therapies, particularly when applied to human patient-derived tissues. The mini-colons' ability to mimic tumor dynamics can reduce our reliance on animal models, which can accelerate the discovery and development of effective treatments.
by Ecole Polytechnique Federale de
Lausanne
Source: Mini-colons advance colorectal cancer research (medicalxpress.com)
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