Cancer metastasis in vitro models – can 3D biofabrication and microfluidics sow the seeds in the right soil

More than 140 years after the first observations that cancer cells spread to secondary sites nonrandomly, the lack of representative pre-clinical models of metastasis precludes our understanding of the processes of metastasis. The development of new 3D biotechnologies, biomaterials, tissue engineering and more intricate in vitro experimental systems, however, can allow for the in-depth study of the main steps of metastasis–invasion, intravasation, circulation in the bloodstream, extravasation and colonization of new sites. In this review, we discuss the improvement of pre-clinical models with a focus on 3D biofabrication and organ-on-a-chip techniques. A systematic and critical description of the current models based on the most common sites of metastasis–the liver, the lungs, the brain and the bones is presented. The current progress in the development of the toolbox to study the mechanisms behind tumour spreading is provided. Several limitations and challenges are also highlighted with the goal to ultimately understand and prevent the major cause of cancer related deaths–metastasis. The convergence of microfluidic chip devices and bioprinting with micrometer precision, together with the implementation of biosensors measuring cellular parameters, can provide tools for the creation of vascularised multi-organ experimental systems. They reflect the complexity of human organs much more accurately than current models and can pave the way for personalised medicine and anti-metastatic drug discovery.