A 3Rs approach to tumour metastasis: investigating the role of cancer stem cells in the metastasis of oral squamous cell carcinoma using an in vitro m

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A 3Rs approach to tumour metastasis: investigating the role of cancer stem cells in the metastasis of oral squamous cell carcinoma using an in vitro microfluidic model 300,000 cases of oral squamous cell carcinoma (OSCC) are diagnosed every year, and around 30% of patients exhibit metastatic spread. Metastasis is a complex process by which cancer cells travel to a secondary site to form a new tumour. Previous work has suggested that cancer stem cells (CSCs) are capable of driving metastasis by switching between epithelial and mesenchymal states. However, the role they play in the interactions with the vascular system, a key component of the tumour microenvironment (TME) recognised to greatly influence metastasis, remains unclear. Here, I used microfluidic devices, a promising new in vitro model, to study these interactions. I fabricated these devices using photolithography and soft lithography techniques and used them to co-culture endothelial cells with OSCC cells in a fibrin gel, to assess the interactions between these two cell types in 3d. After developing and optimising this OSCC metastasis-on-a-chip model, I uncovered a two-way communication between cancer cells and endothelial cells that greatly changes the behaviour of both cell types. Most interestingly, cancer cell invasion undergoes marked changes and is significantly reduced in the presence of endothelial cells. Imaging of the matrix shows that endothelial cells degrade and remodel the matrix when undergoing sprouting angiogenesis in the fibrin gel. This remodelled environment restricts OSCC cell migration in the matrix, and full epithelial-to-mesenchymal transition (EMT) is suppressed - instead invasion progresses through streaming of epithelial tumour cells through pre-existing tracks made by endothelial cells. Immunofluorescent staining of the cells in the invasive streams demonstrates features that have been associated with partial EMT in metastatic CSCs. These findings may represent the generation of a vascular niche that acts to modify the surrounding TME and, through this, influences the invasive CSC phenotype.