title: Nuclear translocation of FGFR1 and FGF2 in pancreatic stellate cells facilitates pancreatic cancer cell invasion.
abstract: Pancreatic cancer is characterised by desmoplasia, driven by activated pancreatic stellate cells (PSCs). Over-expression of FGFs and their receptors is a feature of pancreatic cancer and correlates with poor prognosis, but whether their expression impacts on PSCs is unclear. At the invasive front of human pancreatic cancer, FGF2 and FGFR1 localise to the nucleus in activated PSCs but not cancer cells. In vitro, inhibiting FGFR1 and FGF2 in PSCs, using RNAi or chemical inhibition, resulted in significantly reduced cell proliferation, which was not seen in cancer cells. In physiomimetic organotypic co-cultures, FGFR inhibition prevented PSC as well as cancer cell invasion. 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.
authors: Centre for Tumour Biology Barts Cancer Institute - a CRUK Centre of Excellence, Queen Mary University of London, London, UK.
authors: Stacey J
authors: SJ
authors: Coleman
authors: Athina-Myrto
authors: AM
authors: Chioni
authors: Mohammed
authors: M
authors: Ghallab
authors: Rhys K
authors: RK
authors: Anderson
authors: Nicholas R
authors: NR
authors: Lemoine
authors: Hemant M
authors: HM
authors: Kocher
authors: Richard P
authors: RP
authors: Grose
mesh_terms: D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D058954:Pancreatic Stellate Cells / Q000201:enzymology / Q000378:metabolism*; D021381:Protein Transport; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism*; D059016:Tumor Microenvironment
chemical_list: D016222:Fibroblast Growth Factor 2; D051496:Receptor, Fibroblast Growth Factor, Type 1