Researchers have developed three-dimensional (3D) human tissue culture models of paediatric and adult brain cancers in a brain-mimicking microenvironment.
The development, led by a team of Tufts University researchers, is a significant advancement for the study of brain tumour biology and pharmacological response. The study was published today in Nature Communications.
3D tissue models of brain tumours
The researchers created models that include brain-derived extracellular matrix (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 tumour progression, which in turn alters patterns of genetic and protein expression in the tumour cells.
Earlier studies have noted this important two-way interaction between tumour cells and the surrounding ECM and observed that the protein composition in the ECM can either prevent or allow the further diffusion of tumour cells in the brain. In order to better understand the dynamic interactions between tumours and the ECM, the study authors developed a 3D in vitro system in which they can examine different ECM components and define their contribution to tumour development, as well as tumour response to drug treatments.
The study focused on two common types of brain tumours, both with particularly dismal prognoses – ependymoma, which occurs in young children, and glioblastoma in adults, which results in a median survival of 1-2 years post diagnosis.
In an important advance, the ECM-containing 3D matrix in this study has allowed for the propagation and study of primary tumour cells taken directly from the patient, and to grow them in an environment more similar to the brain.
Previous studies examined established tumour cell lines – not necessarily the tumour of interest – on 3D scaffolds or spheroids without the ECM, or spread cells out in two dimensions (plating), eliciting cell behaviour not seen in their natural environment
David Kaplan, Stern Family Professor of Engineering, chair of the Department of Biomedical Engineering at Tufts’ School of Engineering and program faculty member at the Sackler School of Graduate Biomedical Sciences, said: “The power of this platform is that we can tune the composition of the ECM to find out the role of each component in tumour growth, and we can see the effect on tumour cells derived directly from the patient.
“Another important feature is that we can track the 3D growth of cells with non-invasive two-photon excited fluorescence metabolic imaging via the contributions of Irene Georgakoudi’s team on the project. In other words, we can use non-invasive 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 foetal ECM, which contains higher levels of collagen, HA and certain CSPGs, was better at supporting tumour growth than adult ECM in the 3D cultures (both foetal 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 ‘foetal-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 behaviour of brain tumours in the lab.
Disha Sood, graduate student in Kaplan’s lab and first author of the study, said: “With this platform, we have the potential to better understand what dictates the invasive behaviour of brain tumours and screen drugs for their effect on tumour growth of patient-derived cells.
“Although it’s a preliminary notion, the ability to maintain viable cultures of patient-derived tumour cells and metabolically track them non-invasively, suggests the possibility of monitoring the cells’ behaviour and drug sensitivity over time, to inform treatment decisions.”
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.