Brain metastasis organoids: A systematic review of their methods and clinical application

Brain metastasis represents an ongoing clinical challenge with high morbidity and mortality despite improvements in other areas of oncology. A significant obstacle in brain metastasis research concerns the modelling of the complex tumour-brain microenvironment and there has been a recent shift to the development of more complex assays to improve translational potential. Organoids are three-dimensional tissue aggregates derived from tumour tissue or stem cells and have been utilised extensively in wider biological research. This review aims to summarise the current state of brain metastasis organoid research, with a focus on methodologies, mechanistic understanding, and clinical applicability. A narrative review of the literature was performed using MEDLINE, EMBASE, Scopus, PubMed, ScienceDirect and Web of Science and results were screened using PRISMA guidelines. Search strategies included variations of 'brain metastasis' and 'cerebral organoid' and fifteen articles were included for review. There was a clear lack of uniformity in the methodologies used in organoid production, with additionally fragmented approaches in the investigation of molecular mechanisms and drug discovery. Comparison is thus highly challenging, and this is exacerbated by small sample sizes and diverse primary tumour types. Additionally, there remains an over-reliance on the use of animal-based tissues rather than those derived from human patients. Interestingly, several studies introduced blood-brain-barrier models which show potential however remain in early stages of development. Future studies should aim to streamline organoid production techniques and establish a consensus on relevant molecular pathways of interest, while increasing cohort sizes to enhance clinical applicability. Although it remains in nascent stages, cerebral organoid research represents a field with strong potential to improve knowledge and treatment options for people living with brain metastases.