Abstract The highly invasive phenotype of High Grade Glioma (HGG) brain tumours causes damage to healthy brain tissue as they traverse the brain, and complicates eradication by surgery and radiotherapy. Anti-invasive therapies may therefore help to contain tissue damage and improve therapeutic options. However, there has been limited successful translation of anti-invasive therapies and there are risks of off-target effects, especially in cases where the agent results in the collapse of the actin-cytoskeleton that underpins many healthy tissue functions. In the present study, we have tested the anti-invasive effects of the omega 3 polyunsaturated fatty acid epoxide derivative P-tolyl-ureidopalmitic acid (PTU). We have used 3D in vitro assays to mimic the in vivo tissue microenvironment, including HGG multicellular tumour spheroids (MCTS) embedded in Matrigel and bioprinted cell/matrix combinations with stiffness’ tuned to match brain tissue. Cell imaging reveals that PTU reduces HGG cell dissemination in 3D cultures, inducing cell rounding that reflects a loss of filamentous actin. Anti-invasive effects were further confirmed in assembloid co-cultures consisting of HGG MCTS cultured together with embryonic stem cell-derived cortical organoids. However, immunofluorescence and GeoMxR Digital Spatial Profiling of assembloid co-cultures reveals that PTU also disrupts signalling in the ‘healthy’ cortical organoid. Thus, combined use of culture models that mimic aspects of the tumour microenvironment facilitated evaluation of in vivo relevant cell invasion, and, concurrent assessment of potential off-target effects. Collectively, the data suggests a useful methodological approach for investigating the efficacy and safety of potential anti-invasive therapies for HGG.
Sarker et al. (Fri,) studied this question.