The progression of brain tumors cannot be staged properly without adequate stagecraft—stagecraft so thorough and technically adept that the distinction between players and props becomes blurred. The players, or cancer cells, will not hit their marks unless the marks are, well, marked. Only then will the players be in a position to take their cues or hear their lines being fed to them.

Masters of stagecraft at Tufts University have demonstrated that in the modeling of brain tumors, the players perform most convincingly if they can interact with the most realistic extracellular matrix (ECM). Think of ECM as the scenery, the costumes, the props, the lighting—all of it adjusted as needed.

Emerging from backstage, a Tufts-led team of researchers has presented a tunable 3D bioengineered brain tissue platform. It integrates microenvironmental cues of native brain-derived ECMs and live imaging to systematically evaluate patient-derived brain tumor responses.

Details appeared October 4 in Nature Communications in an article titled, “3D extracellular matrix microenvironment in bioengineered tissue models of primary pediatric and adult brain tumors.” As the “3D” suggests, this approach is designed to enable brain tumor modeling in the round.

“[Our] versatile bioengineered 3D tumor tissue system sets the stage for mechanistic studies deciphering microenvironmental role in brain tumor progression,” the article’s authors wrote. This system allows researchers to examine different ECM components and define their contribution to tumor development, as well as tumor response to drug treatments.

Using this system, the Tufts-led team created models that include brain-derived ECM, the complex network of proteins and amino acids with bound sugars naturally found in the brain. The ECM not only provides support for surrounding neural tissue, but also helps to guide cell growth and development. Alterations in ECM composition have been associated with brain tumor progression, which in turn alters patterns of genetic and protein expression in the tumor cells.

“Using pediatric ependymoma and adult glioblastoma as examples, the 3D brain ECM-containing microenvironment with a balance of cell-cell and cell-matrix interactions supports distinctive phenotypes associated with tumor type-specific and ECM-dependent patterns in the tumor cells’ transcriptomic and release profiles,” the article’s authors wrote. “Label-free metabolic imaging of the composite model structure identifies metabolically distinct sub-populations within a tumor type and captures extracellular lipid-containing droplets with potential implications in drug response.”

Earlier studies have noted this important two-way interaction between tumor cells and the surrounding ECM, and observed that the protein composition in the ECM can either prevent or allow the further diffusion of tumor cells in the brain. These studies, however, usually examined established tumor cell lines—not necessarily the tumor of interest—on 3D scaffolds or spheroids without the ECM, or spread cells out in two dimensions (plating), eliciting cell behavior not seen in their natural environment.

In the current study, the ECM-containing 3D matrix allowed for the propagation and study of primary tumor cells taken directly from the patient, and to grow them in an environment more similar to the brain.

“The power of this platform is that we can tune the composition of the ECM to find out the role of each component in tumor growth, and we can see the effect on tumor cells derived directly from the patient,” said Tuft’s David L. Kaplan, PhD, the Stern family professor in engineering and the study’s senior author. “Another important feature is that we can track the 3D growth of cells with noninvasive two-photon excited fluorescence metabolic imaging. In other words, we can use noninvasive imaging to assess if they are viable and growing, or stressed and dying, in real time.”

Among the findings revealed in the study was that fetal ECM, which contains higher levels of collagen, hyaluronan, and certain chondroitin sulfate proteoglycans, was better at supporting tumor growth than adult ECM in the 3D cultures (both fetal and adult ECMs were derived from pig brains). That result correlates with the notion that brain cancers tend to alter the ECM so its composition becomes more “fetal like” to support their growth, according to the researchers.

Another key finding was the appearance of lipid (fat) droplets being released by the adult glioblastoma cells which may contribute to lowering the drug sensitivity of many glioblastoma cells (possibly by absorbing the drugs). This may be correlated with poor survival both in the 3D tissue model and in patients. The droplets have not been observed in vitro prior to these experiments, suggesting that this model is a robust system to study the behavior of brain tumors in the lab. The application of engineering solutions (in this case, the development of a 3D silk-based matrix) to improve the study of the brain is a collaborative effort taken on by the authors as part of the Initiative for Neural Science, Disease & Engineering (INSciDE@Tufts).

“With this platform, we have the potential to better understand what dictates the invasive behavior of brain tumors and screen drugs for their effect on tumor growth of patient-derived cells,” said Disha Sood, graduate student in Kaplan’s lab and first author of the study. “Although it’s a preliminary notion, the ability to maintain viable cultures of patient-derived tumor cells and metabolically track them noninvasively, suggests the possibility of monitoring the cells’ behavior and drug sensitivity over time, to inform treatment decisions.”

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