Nuclear translocation of FGFR1 and FGF2 in pancreatic stellate cells facilitates pancreatic cancer cell invasion

• Published in: EMBO molecular medicine 2014-04, Vol.6 (4), p.467-481
• Main Authors: Coleman, Stacey J, Chioni, Athina‐Myrto, Ghallab, Mohammed, Anderson, Rhys K, Lemoine, Nicholas R, Kocher, Hemant M, Grose, Richard P
• Format: Article
• Language: English
• Subjects: Cell Line, Tumor; Cell Nucleus - enzymology; Cell Nucleus - genetics; Cell Nucleus - metabolism; Cell Proliferation; EMBO03; EMBO12; FGF signalling; Fibroblast Growth Factor 2 - genetics; Fibroblast Growth Factor 2 - metabolism; human cancer; Humans; invasion; Neoplasm Invasiveness; organotypic cultures; Pancreatic Neoplasms - enzymology; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - physiopathology; Pancreatic Stellate Cells - enzymology; Pancreatic Stellate Cells - metabolism; Protein Transport; Receptor, Fibroblast Growth Factor, Type 1 - genetics; Receptor, Fibroblast Growth Factor, Type 1 - metabolism; Research Article; Tumor Microenvironment
• ISSN: 1757-4676; 1757-4684
• DOI: 10.1002/emmm.201302698

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. Synopsis Chemical or RNAi‐mediated inhibition of nuclear FGFR1 and FGF2 leads to disruption of the tumour‐supportive microenvironment provided by pancreatic stellate cells thus preventing pancreatic cancer cell invasion. Nuclear FGFR1 and FGF2 are apparent in the stromal fibroblasts at the invasive front of human pancreatic cancer. In vitro FGFR1 and FGF2 co‐localise to the nucleus in pancreatic stellate cells but not pancreatic cancer cells and are essential for proliferation and invasion. Blocking nuclear FGFR1 and FGF2 results in a significant reduction in proliferation of pancreatic stellate cells and has a significant effect on invasion of pancreatic cancer cells in a 3D organotypic model of pancreatic cancer. Graphical Abstract Chemical or RNAi‐mediated inhibition of nuclear FGFR1 and FGF2 leads to disruption of the tumour‐supportive microenvironment provided by pancreatic stellate cells thus preventing pancreatic cancer cell invasion.