|dc.description.abstract||Patients who are diagnosed with pancreatic ductal adenocarcinoma (PDAC) face a dismal prognosis. One reason for this is the dense stroma that is a characteristic of PDAC, which may preclude drugs from accessing the tumour cells. Pancreatic stellate cells (PSCs) are the key cell responsible for desmoplasia in PDAC and it is becoming clear that they are a promising target for therapy. Over-expression of FGFs and their receptors is a feature of PDAC and correlates with poor prognosis, but whether their expression impacts on PSCs is unclear. The aim of my research was 1) to understand the role and function of nuclear FGFR1 and FGF using 2D based assays; 2) to use a physiologically relevant 3D organotypic model to study the effects of blocking nuclear FGFR1 and FGF2 in PSCs; 3) to assess whether this target could provide a novel therapeutic strategy in PDAC.
At the invasive front of human pancreatic cancer, FGF2 and FGFR1 localised to the nucleus in activated PSCs but not cancer cells. Inhibiting FGFR1 and FGF2 in PSCs, using RNAi or chemical inhibition in vitro, resulted in significantly reduced cell proliferation, which was not seen in cancer cells. Cancer cells co-cultured on top of collagen/Matrigel gels together with PSCs showed marked invasion of both cancer cells and PSCs. However, FGFR inhibition blocked invasion of both PSCs and cancer cells. FGFR inhibition resulted in cytoplasmic localisation of FGFR1 and FGF2, in contrast to vehicle-treated conditions where PSCs with nuclear FGFR1 and FGF2 led cancer cells to invade the underlying extra-cellular matrix. Strikingly, abrogation of nuclear FGFR1 and FGF2 in PSCs abolished cancer cell invasion. These findings suggest a novel therapeutic approach, where preventing nuclear FGF/FGFR mediated proliferation and invasion in PSCs leads to disruption of the tumour microenvironment, preventing pancreatic cancer cell invasion. Thus, for
patients with PDAC which is resistant to conventional chemotherapy, targeting the stroma by blocking nuclear FGFR1 and FGF2 in PSCs identifies a novel therapeutic approach.||en_US