The tumour microenvironment is complex and formed of multiple cell types, non-cellular components and interstitial fluid. The development of a tumour is guided by interactions in the microenvironment including the dynamics of interstitial fluid, microcirculation of blood vessels and the immune system. This complexity leads to tumour heterogeneity and heterogeneity between tumours of various origins and at differing stages of progression. Development of new therapeutics relies on screening in an accurate recapitulation of a tumour and the microenvironment in which it resides, which is currently not reflected in preclinical models.
Why we funded it
This training fellowship aims to replace the requirement of animals for preclinical drug validation by developing a bioreactor culture platform to more accurately represent a tumour microenvironment.
Approximately 2,300 mice per year are used in oncological preclinical validation studies at the University of Oxford, with the majority of studies using therapeutics proven efficient in two-dimensional in vitro models. After in vivo studies ~60% of cancer therapeutics are excluded due to ineffectiveness. Using the bioreactor system has the potential to reduce attrition of cancer therapeutics by providing a better setting for in vitro preclinical studies. If all drugs that are likely to be excluded during in vivo studies were identified earlier by in vitro screening, then animal usage in preclinical drug validation studies could be reduced to ~900 animals per year at the University of Oxford alone.
Dr Wan and colleagues have developed a prototype bioreactor culture platform capable of supporting 3D “micro-tissues” formed either from established cancer cell lines or from small amounts of patient tissue1. The small amount of tissue needed makes this system ideal for sustaining cancers isolated from the brain or pancreas as clinical samples are rare. Micro-tissues can be cultured in combination with other cells from the microenvironment, such as immune cells, in a spatiotemporal manner. The bioreactor design also incorporates the perfusion of culture media to mimic the flow of the interstitial environment of tumours and resultant fluid dynamics. Dr Wan will validate the in vitro culture system by treating with cancer therapeutics known to impact the tumour microenvironment and observing effects on the micro-tissue. This system allows for screening and validation of cancer therapeutics in a physiologically relevant microenvironment prior to in vivo testing.
Wan X et al. (2019). An Improved In Vivo Angiogenesis Model of Chicken Chorioallantoic Membranes in Surrogate Shells Revealed the Pro-angiogenesis Effects of Chylomicrons. Vascular Cell 11(1):1. doi: 10.24238/13221-11-1-178
Wan X et al. (2017). Morphological analysis of human umbilical vein endothelial cells co-cultured with ovarian cancer cells in 3D: An oncogenic angiogenesis assay. PLOS ONE 12(7):e0180296. doi: 10.1371/journal.pone.0180296
Wan X et al. (2017). Perfused Three-dimensional Organotypic Culture of Human Cancer Cells for Therapeutic Evaluation. Scientific Reports 7(1):9408. doi: 10.1038/s41598-017-09686-0