【摘 要】
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There is a growing body of evidence showing that FGFRs can be targeted to the nucleus.We investigate FGFR signalling in breast and pancreatic cancer cell line models, complementing these studies with
【机 构】
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Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London,London EC1M 6BQ,
【出 处】
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3rd International Conference on Fibroblast Growth Factors (F
论文部分内容阅读
There is a growing body of evidence showing that FGFRs can be targeted to the nucleus.We investigate FGFR signalling in breast and pancreatic cancer cell line models, complementing these studies with study of clinical samples.Focusing on FGFR1, we have identified a novel pathway that mediates invasive behaviour in breast cancer cells.We have shown that a C-terminal fragment of FGFR1, generated by receptor activation-dependent cleavage, traffics to the nucleus and regulates the expression of target genes.Having identified a functional role for nuclear FGFR1 in cell culture models, we showed that this phenomenon also occurs in vivo in invasive breast cancer and have identified a panel of FGFR1-regulated target genes, all of which regulate cell migration and thus could reflect an invasive signature.The role of the stroma in cancer has come under increasing scrutiny recently and pancreatic cancer shows a particularly dramatic stromal response.In pancreatic cancer, a number of FGFs and their cognate receptors are over-expressed and linked to poor prognosis.We have shown that FGF2 and FGFR1 localise to the nucleus in stromal fibroblasts of human pancreatic cancer tissue as well as in pancreatic stellate cell (PSC) lines.In an organotypic model, nuclear FGFR1 and FGF2 increased in PSCs invading underlying stroma and, upon FGFR inhibition, PSCs were unable to invade and FGFR1 and FGF2 remained cytoplasmic, and cancer cell invasion was abolished.Thus, preventing nuclear FGF/FGFR mediated proliferation in PSCs leads to disruption of the tumour microenvironment, preventing pancreatic cancer cell invasion.
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