Pancreatic ductal adenocarcinoma (PDAC) is predicted to be the second leading cause of cancer mortality by 2030. Current standard-of care gemcitabine/Abraxane is only marginally improved over previous monotherapy regimes, which are generally ineffective in this aggressive treatment-refractory disease. PDAC development occurs in a complex microenvironment, where extensive stromal desmoplasia alters mechanical tumour-stromal interactions promoting tumour progression and metastatic spread. In highly metastatic mouse models of PDAC, we observe enhanced extracellular matrix (ECM) deposition and remodelling throughout disease progression, which occurs in parallel with increased Focal Adhesion Kinase (FAK) expression and activity.
Stratified patient samples suggest a subset of patients with high FAK activity are likely to respond to FAK priming regimes, where fine-tuned ECM manipulation prior to chemotherapy may improve patient outcome.Consequently, we aim to fine-tune FAK inhibition (FAKi) of both the tumour and stromal compartments in primary, transient and secondary sites, while improving global response to standard-of-care. Intravital imaging of the FUCCI cell cycle reporter at secondary sites, post intrasplenic injection, was used to systematically demonstrate that FAKi modulates the ECM whilst also sensitising cells to shear stress prior to standard-of-care therapy, enhancing treatment efficacy whilst reducing metastatic spread. To assess the response of cells to FAKi, we measured real time treatment response in vivowith a Förster resonance energy transfer (FRET) biosensor for FAK activity. Here, parallel imaging of collagen by Second Harmonic Generation facilitated dynamic monitoring of tumour cell response to FAKi inhibition in the context of ECM organisation. This subtype-specific fine-tuned stromal manipulation may allow us to maximise gemcitabine/Abraxane therapy whilst reducing drug toxicity and potentially reducing further metastatic spread in patients.