3D Bone Morphology Alters Gene Expression, Motility, and Drug Responses in Bone Metastatic Tumor Cells

Abstract

Patients with advanced skeletal metastases arising from primary cancers including breast, lung, and prostate suffer from extreme pain, bone loss, and frequent fractures. While the importance of interactions between bone and tumors is well-established, our understanding of complex cell–cell and cell–microenvironment interactions remains limited in part due to a lack of appropriate 3D bone models. To improve our understanding of the influence of bone morphometric properties on the regulation of tumor-induced bone disease (TIBD), we utilized bone-like 3D scaffolds in vitro and in vivo. Scaffolds were seeded with tumor cells, and changes in cell motility, proliferation, and gene expression were measured. Genes associated with TIBD significantly increased with increasing scaffold rigidity. Drug response differed when tumors were cultured in 3D compared to 2D. Inhibitors for Integrin β3 and TGF-β Receptor II significantly reduced bone-metastatic gene expression in 2D but not 3D, while treatment with the Gli antagonist GANT58 significantly reduced gene expression in both 2D and 3D. When tumor-seeded 3D scaffolds were implanted into mice, infiltration of myeloid progenitors changed in response to pore size and rigidity. This study demonstrates a versatile 3D model of bone used to study the influence of mechanical and morphometric properties of bone on TIBD.

How the “seed” prepares the “soil”: the bone/bone marrow pre-metastatic niche

“…Recently, Waning et al [108] demonstrated that TGFβ released from bone also contribute to muscle weakness in an in vivo model of bone metastases. In line with this, inhibition of TGFβ and its signaling pathway leads to increased bone mass [109] , thus paving the way for possible therapeutic applications [110,111] .…”

Organoid Models and Next-Generation Sequencing for Bone Marrow and Related Disorders

“…Genetics and gene expression are one of the main factors used to investigate changes in diseases. Studies investigating prostate cancer bone metastases and tumour-induced bone diseases (TIBD) have reported variations in the expression of genes when compared in 2D than in 3D [96,97], further outlining the need for 3D in vitro models.…”

A glitch in the matrix: organ-specific matrisomes in metastatic niches

“…The decellularized matrices can also be used to coat scaffold biomimics, allowing for a more accessible comparison of ECM effects in different disease states [81]. Scaffolds were also used to study bone metastasis in vitro and in vivo to determine how changes in pore size and rigidity affect myeloid cell infiltration, gene expression, and drug response [82]. These advancements in analysis approaches have inspired new uses for oncomaterials in monitoring disease progression and treating patients [83].…”