Interactions between cancer cells and their surrounding microenvironment play a critical role in tumour progression. Focal adhesion kinase (FAK), a key mediator in transducing external signals from the surrounding microenvironment, reinforces positive feedback loops that accompany extracellular matrix (ECM) remodelling. FAK expression and activity is widely increased in primary and metastatic cancers, including pancreatic ductal adenocarcinoma (PDAC), which is predicted to be the second highest cause of cancer mortality by 2030. In the highly metastatic KPC model of PDAC, we observed enhanced ECM deposition and remodelling throughout disease progression, in parallel with increased FAK expression and activity.
Here we assessed the potential of transient stromal ‘priming’ prior to standard-of-care therapy, gemcitabine/Abraxane, to enhance treatment efficacy; and that FAK-inhibition can target several aspects of cancer invasiveness. Using 3D models that mimic the native tumour ECM and state-of-the-art imaging technologies to dynamically monitor and streamline FAK ‘priming’ regimes, we have shown that FAK inhibition reduces fibroblast-mediated ECM remodelling, breaking pro-tumorigenic tumour-ECM feedback loops and decreasing PDAC cell invasion and metastatic spread. In line with this, our data suggests that FAK-inhibition sensitises PDAC cells to anchorage-independent growth conditions and shear stress, potentially impairing the ability of circulating tumour cells to survive in the vasculature and colonise distant sites. Furthermore, using the FAK-Fluorescence resonance energy transfer biosensor as a pre-clinical tool, we have directly measured the response of PDAC cells and fibroblasts to FAK-inhibition in real time. Lastly, to more clearly recapitulate the heterogeneity of human PDAC, we have profiled and stratified samples from our in-house PDAC tissue microarrays, patient-derived xenograft (PDX) models and matching cell lines (PDCL), for high/low FAK expression and activity. Graded, subtype-specific response to FAK manipulation allowed us to identify a subset of PDX/PDCLs likely to respond to FAK ‘priming’, prior to standard-of-care chemotherapy. This subtype-specific fine-tuned stromal manipulation may allow us to maximise gemcitabine/Abraxane therapy whilst reducing drug toxicity and potentially reducing metastatic spread on a clinically relevant basis.