The extracellular matrix (ECM) provides cancer cells with a 3D structural and biochemical scaffold that regulates cellular function and behaviour. Pancreatic Ductal Adenocarcinoma (PDAC) is characterised by its aggressive metastatic nature and a dense, desmoplastic ECM. which has been identified to both promote and prevent PDAC development. Compounded with late diagnosis, another major factor contributing to the poor survival rates in PDAC is the rapid and early spread of the disease in regional and distant organs.
The multifunctional protein, focal adhesion kinase (FAK), is at the intersection of various pathways often hijacked in cancer and is a known regulator of ECM stiffness and mechano-signalling in both stromal and epithelial compartments. In the highly metastatic mouse models of PDAC, we observe enhanced ECM deposition and remodelling throughout disease progression, which occurs in parallel with increased Focal Adhesion Kinase (FAK) expression and activity.
Utilising 3D-organotypic matrices in parallel with advanced imaging techniques as a high-fidelity platform to streamline treatment regimes, we fine-tune epithelial and stromal manipulation via FAK inhibition and improve systematic chemotherapeutic efficiency whilst reducing metastatic spread. Here, intravital imaging of the FUCCI cell cycle reporter, in parallel with Second Harmonic Generation imaging of collagen fibres, was used to dynamically monitor tumour cell response to Gemcitabine/Abraxane and FAK driven ECM manipulation, respectively, at both primary and secondary sites.
Furthermore, stratified patient samples suggest a subset of patients with high FAK activity are likely to respond to FAK treatment regimes, where fine-tuned ECM manipulation and epithelial FAK inhibition prior to chemotherapy may improve patient outcome. This fine-tuned stromal manipulation may allow us to maximise Gemcitabine/Abraxane therapy whilst reducing drug toxicity associated with combinational treatment and potentially reducing further metastatic spread in patients.