Scalable biomanufacturing of tumor organoids

Abstract

Disclosed herein are matrix-free and in vivo-like glioblastoma organoids (GBOs) developed using patient-derived xenograft GBM lines in small-scale bioreactors and a method of scalable biomanufacture thereof. Shear stress, agitation rate, and media supplements can be optimized to produce highly reproducible GBOs over 1 mm diameter within 4-5 weeks. GBOs can exhibit high stemness and strong cell-to-cell interactions compared to conventional tumorsphere cultures. They can display spatial gradients of HIF-1α positive hypoxic cores where CD133-positive cells resided and spatially heterogeneous expression of NOTCH and its ligands. A self-established, hierarchically organized, and heterogeneous TME by GBM transdifferentiation into endothelial cells, pericytes, and astrocytes can also be observed. Collectively, the ability to biomanufacture uniformly sized GBOs that recapitulate in vivo GBM TME features that can serve as an improved GBM in vitro model is demonstrated herein.

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