3D geometry orchestrates the transcriptional landscape of metastatic neuroblastoma cells in a multicellular bone model.

A key challenge for the discovery of novel molecular targets and therapeutics against pediatric bone metastatic disease is the lack of bona fide cell models. Here, we show that a beta-tricalcium phosphate (β-TCP) multicellular 3D bone microtissue model reconstitutes key phenotypic and transcriptional patterns of native metastatic tumor cells while promoting their stemness and proinvasive features. Comparing planar with interconnected channeled scaffolds, we identified geometry as a dominant orchestrator of proangiogenic traits in neuroblastoma tumor cells. On the other hand, the β-TCP-determined gene signature was DNA replication related. Jointly, the geometry and chemical impact of β-TCP revealed a prometastatic landscape of the engineered tumor microenvironment. The proposed 3D multicellular model of pediatric bone metastatic disease may advance further analysis of the molecular, genetic and metabolic bases of the disease and allow more efficient preclinical target validations.