Cancer treatment can sometimes resemble an intricate dance. Despite treatments seeming to work initially, the evolving nature of tumours allow cancer to progress in defiance of therapeutic efforts.
Take glioblastoma (GBM), an aggressive brain tumour, for example. Its resistance to the first-line chemotherapy drug temozolomide (TMZ) is not solely due to GBM’s genetic makeup; the tumour’s spatial organisation within the cerebral context, and the protective barrier of the blood-brain barrier (BBB), are both known influencers of drug resistance.
Andrea Pavesi, a Principal Investigator at A*STAR’s Institute of Molecular and Cell Biology (IMCB), observed that these are just some of the molecular pathways in the complex landscape of TMZ resistance. “A better understanding of these pathways would lead to better patient stratification and inform the design of new drugs,” said Pavesi.
Conventionally, animal models are employed to investigate the underpinnings of tumour drug resistance. However, these may not accurately reflect human-specific pathways, and experiments that use them also tend to be lengthy and expensive, said Maxine Lam, an IMCB Senior Scientist.
Seeking an alternative to animal models, “advancements in cell culture techniques and bioengineering have led to the development of 'organ-on-a-chip' technologies, where cells are cultured in microfluidic devices that enable researchers to rebuild the tumour's spatial complexity,” Lam added.
With this imperative, Lam, Pavesi and their IMCB colleagues worked with researchers from the National Neuroscience Institute, Singapore, to develop a novel in vitro microfluidic device that integrates human cells (including primary brain endothelial cells, astrocytes and pericytes) to mimic interactions between GBM and the BBB. Lam and Pavesi were first and corresponding authors of the study, respectively.
The model was designed to capture GBM’s key anatomical features, including the BBB’s vascular network and the tumour’s spatial organisation. By applying their model, the team showed that 3D clusters of patient-derived GBM cells affected vasculature organisation and promoted blood vessel growth, highlighting the complex interplay between GBM and the BBB in the tumour’s biology.
“Our model can provide an accurate means of therapy validation by studying how the tumour microenvironment (TME) affects treatment resistance,” said Lam, noting this research tool can be rapidly synthesised in a one-week timeframe for drug evaluation.
The team also developed novel workflows for the in vitro microtissues to identify proteins involved in tumorigenesis and TMZ resistance. "The presence of the brain vasculature altered the GBM tumours’ biology, making them even more aggressive and resistant to treatment,” said Pavesi.
Pavesi added that the work was made possible thanks to Radoslaw Sobota, a Principal Investigator at IMCB's Functional Proteomics Laboratory (FPL). The FPL partnership led to the discovery that a shift in GBM protein expression—including proteins involved in cell division—occurred after exposure to TMZ, which points to a possible mechanism by which GBM becomes more aggressive and resists treatment.
Together, these findings underscore the TME’s critical role in developing treatments for glioblastoma and introduces a valuable tool to investigate the mechanisms of GBM progression and next-generation GBM therapies. Moving forward, the team intends to extend their molecular profiling to identify prospective therapeutic targets, thereby forging pathways towards more effective treatments.
The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology (IMCB).
