Three-Dimensional Organoids in Cancer Research: The Search for the Holy Grail of Preclinical Cancer Modeling.

Most solid tumors become therapy resistant and will relapse, with no durable treatment option available. One major impediment to our understanding of cancer biology and finding innovative approaches to cancer treatment stems from the lack of better preclinical tumor models that address and explain tumor heterogeneity and person-to-person differences in therapeutic and toxic responses. Past cancer research has been driven by inadequate in vitro assays utilizing two-dimensional monolayers of cancer cells and animal models. Additionally, animal models do not truly mimic the original human tumor, are time consuming, and usually costly. New preclinical models are needed for innovation in cancer translational research. Hence, it is time to welcome the three-dimensional (3D) organoids: self-organizing cells grown in 3D culture systems mimicking the parent tissues from which the primary cells originate. The 3D organoids offer deeper insights into the crucial cellular processes in tissue and organ formation and pathological processes. Generation of near-perfect physiological microenvironments allow 3D organoids to couple with gene editing tools, such as the clustered regularly interspersed short palindromic repeat (CRISPR)/CRISPR-associated 9 and the transcription activator-like effector nucleases to model human diseases, offering distinct advantages over current models. We explain in this expert review that through recapitulating patients' normal and tumor tissues, organoid technology can markedly advance personalized medicine and help reveal once hidden aspects of cancers. The use of defined tissue- or organ-specific matrices, among other factors, will likely allow organoid technology to realize its potential in innovating many fields of life sciences.