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Left: Image of a soft hydrogel with normal developing cell cultures (full triangles). Right: Image of a reinforced hydrogel resembling a tumor with transformed cells (open triangles). Credit: Matt Ondeck and Jesse Placone
A study provides new information on how bad tissue building plays a role in the development of bad cancer. By examining how bad cells respond in a hydrogel that changes stiffness, bioengineers at the University of California at San Diego have discovered that several pathways are contributing to the transformation of bad cells into cancer cells. The work could inspire new approaches to treat patients and inhibit tumor growth.
The team presented its findings in an article published online on February 12 in the minutes of the National Academy of Sciences (PNAS).
"By dynamically modulating the rigidity of the microenvironment, we can better mimic what happens when bad cells are transformed into a malignant state in a dish," said lead author Adam Engler, a professor of bioengineering at the University of California. San Diego Jacobs School of Engineering. .
The study is part of a growing body of research showing that mechanical forces – not just genetic and biochemical cues – play a key role in the development and spread of cancer. In the past, researchers have found that modeling in vitro rigid tissue environments promotes tumor growth.
But these models often do not fully recreate what is happening in the body because they are static, noted Engler. "Tissue stiffening is a dynamic process – bad tissue does not start to be stiff, it's something that develops over time," Engler said.
Engler's approach was therefore to use a hardware system in which rigidity could be dynamically adjusted when the cells were inside, and then to see how cells reacted to this change in rigidity.
"We try to mimic the process of fibrosis during the progression of tumor development," said Jesse Placone, a postdoctoral researcher in Engler's lab and co-lead author of the study. "As a tumor site is formed, the local stiffness of the tissue increases, and by modeling this dynamic rigidity, our system is much more representative of what happens in vivo."
The team used a hydrogel called methacrylated hyaluronic acid, a soft material that can be stiffened to varying degrees by exposure to free radicals and ultraviolet light. They first stiffened the hydrogel sufficiently to mimic the stiffness of normal bad tissue. Then they grew mammary epithelial cells in the gel. Once cells have matured, the rigidity of the gel has been increased to that of a bad tumor. The team noted that the UV exposure required at this stage was not sufficient to harm the cells.
They discovered that rigidity triggers multiple pathways that together signal to bad cells to become cancerous. The main players in these pathways include TWIST1, TGF-beta, SMAD and YAP proteins.
"In a dynamic environment, we have found that these different pathways act in cooperation, and it is not enough to inhibit just one of these pathways, as has been demonstrated in modeling studies of static and rigid environments. "said Engler. "From a clinical point of view, this suggests that a single drug approach might not work in all patients with bad cancer tumors."
The team also discovered that a subpopulation of bad cells did not respond to stiffness. Engler said that it was good news for women because fewer cells than previously thought could turn into cancer solely because of the environment. Such a result, if it results for patients, could mean fewer or fewer primitive tumors.
The team then plans to explore drug candidates to inhibit these pathways and study their effects on tumor progression. This research was conducted mainly on genetically controlled cell lines. The team will therefore continue studies on cell lines derived from patients.
This article has been republished from documents provided by the University of California San Diego. Note: Content may have changed for length and content. For more information, please contact the cited source.
Reference: Matthew G. Ondeck, et al. A dynamically stiffened matrix promotes the malignant transformation of mammary epithelial cells via collective mechanical signaling. PNAS. (2019) https://doi.org/10.1073/pnas.1814204116
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