Abstract
A high throughput histology (microTMA) platform was applied for testing drugs against tumors in a novel 3D heterotypic glioblastoma brain sphere (gBS) model consisting of glioblastoma tumor cells, iPSC-derived neurons, glial cells and astrocytes grown in a spheroid. The differential responses of gBS tumors and normal neuronal cells to sustained treatments with anti-cancer drugs temozolomide (TMZ) and doxorubicin (DOX) were investigated. gBS were exposed to TMZ or DOX over a 7-day period. Untreated gBS tumors increased in size over a 4-week culture period, however, there was no increase in the number of normal neuronal cells. TMZ (100 uM) and DOX (0.3 uM) treatments caused ~30% (P~0.07) and ~80% (P < 0.001) decreases in the size of the tumors, respectively. Neither treatment altered the number of normal neuronal cells in the model. The anti-tumor effects of TMZ and DOX were mediated in part by selective induction of apoptosis. This platform provides a novel approach for screening new anti-glioblastoma agents and evaluating different treatment options for a given patient.
Highlights
Drug development costs are high and the process is inefficient[1]
Neuronal cells did not increase in number over this time course, which concurs with their postmitotic differentiation state (Fig. 1B).The histological characteristics of the glioblastoma brain sphere (gBS) glioblastoma tumors were consistent with those observed in xenograft tumors with the same glioblstoma cell line in that they showed high cellularity with a spherical morphology (Figs 1A,a–f and 2C,a,b)
We found staining for the neuronal (Tuj[1] and NF200), astrocyte (GFAP and vimentin) and oligodendrocyte (O1) markers consistent with the presence of these normal brain cell types in the gBS (Fig. 1C,a–i)
Summary
Drug development costs are high and the process is inefficient[1]. Drug companies aim to produce drugs to treat chronic and complex diseases with a high safety margin. Performing high-throughput testing of 3D models is challenging due to difficulties associated with staining and imaging throughout the tissues caused by lack of antibody penetration and fluorescence light scatter and quenching[14,15]. To address this issue, we have developed a spheroid tissue microarray (microTMA) technology. We have for the first time incorporated cells from the most devastating brain cancer (glioblastoma) from primary brain tumor tissue from our patients into the BS. A unique feature of this system is its ability to assess both on-target and off-target effects of drugs as our model incorporates both primary brain tumor cells from our patients and normal neuronal cells (neurons, astrocytes, glial cells)
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