Using a custom-designed spheroid-on chip model to study impact of sheer stress under low oxygen conditions

Project Description

Metastatic, or secondary, cancer has particularly poor prognosis, accounting for up to 90% of all cancer deaths. Therefore, identification and validation of early metastasis biomarkers and/or defining metastasis-specific therapeutic targets is essential to effectively tackle cancer burden. Metastatic disease is known to be driven by characteristics of the local tumour microenvironment, including tumour hypoxia (low oxygen in tumours), cellular composition, extracellular matrix, and interstitial flow.

We have recently developed a ‘spheroid-on-chip’ device to assessment the impact of flow on metastatic spread in vitro. Using this system, we observed that exposure to flow can lead to dramatic changes in gene expression. As predicted, hypoxia-mediated signalling was downregulated in flow, likely due to the improved perfusion of the spheroids. Interestingly, we found that other signalling pathways not linked with hypoxia biology were upregulated in flow, including genome protective pathways, which had not so far been reported in cancer models.

Therefore, the purpose of this study is to evaluate our spheroid-on-chip model in hypoxic conditions, to eliminate the perfusion/reoxygenation element of the flow system, and therefore highlight signalling pathways more unique to flow and uncoupled from the hypoxia/reperfusion-associated signalling changes.

The results from this study will further develop our model to explore interstitial flow biology and signalling, both key factors inherent to the broader tumour microenvironment. Importantly, it will further elucidate novel biomarkers or novel drug targets for interstitial flow biology in tumours independently of hypoxic content, with the ultimate goal of improving patient outcomes.