Multi-omics qualification of an organ-on-a-chip model of osteolytic bone metastasis

Abstract

Bone is a primary site for metastasis in breast cancer, with up to 70 % of patients with metastatic breast cancer developing osteolytic bone lesions, wherein cancer cells drive osteoclast resorption of bone. However, progress in developing therapies is limited by the absence of predictive in vitro models. This study developed a unique organ-on-a-chip model to simulate osteolytic bone metastasis and utilised a multi-omics approach for characterisation/qualification and validation against in vivo data. Using the Emulate S1 platform, we co-cultured murine osteocytes and osteoclasts to recreate the bone microenvironment, alongside breast cancer cells in a separate channel separated by a porous membrane. Using RNA sequencing, cytokine profiling, and fluorescence staining, we demonstrated the importance of the complete tri-culture model in replicating key aspects of in vivo biology, and uncovered critical pathways involved in metastasis. A synergistic effect was observed in the tri-culture organ-chip model, leading to increased cancer cell migration and the upregulation of pro-metastatic and pro-inflammatory pathways that promote bone degradation and cancer progression. This study validates an organ-chip model of osteolytic breast cancer bone metastasis as a scalable alternative to traditional animal models. Furthermore, we show how multi-omics and bioinformatics techniques may be used for qualification and validation of organ-chip models; for unpicking the relative contribution of the different cell types; and to identify signalling pathways and therapeutic targets. STATEMENT OF SIGNIFICANCE: In this study, we develop a 3D organ-on-a-chip tri-culture model of the osteolytic metastatic niche, in which we verify expected bone and breast cancer cell behaviours. Importantly, we successfully validate our organ-chip against a dataset from the gold standard in vivo preclinical model of osteolytic breast metastases, using transcriptomics and proteomics to confirm strong alignment of gene expression profiles with in vivo mouse expression. Additionally, our multi-omics analysis sheds new light on both expected and novel molecular pathways for therapeutic targeting, demonstrating the utility of the organ-chip as a potential replacement for preclinical mouse models of breast cancer metastases in bone. Therefore, this study represents a key marker in the field of organ-chip research, demonstrating the importance of biomaterials technologies for preclinical science. Most importantly, our work demonstrates for biotech and pharma companies that qualified organ-chip devices can play a role as intermediate medium-throughput technologies for screening lead drug candidates.

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