CCB seminar Tuesday the 9th of October at 13-14 hrs Dr. Richard Grose

Novel roles for FGFR1 signalling in breast and pancreatic cancers

Abstract

Fibroblast Growth Factor signalling plays critical roles in development and has been implicated in many different cancers, suggesting that FGF signalling is co-opted by cancer cells. FGFRs are well known to signal from the cell membrane as well as from endosomal compartments but there is a growing body of evidence showing that full-length FGFRs, and FGFR1 in particular, can be targeted to the nucleus. We have used a variety of biochemical, molecular and functional studies to investigate FGFR signalling in breast and pancreatic cancer cell line models, and complemented these studies with immunohistochemical studies of clinical samples.

Focusing largely on FGFR1, we have identified a novel pathway that mediates invasive behaviour in breast cancer cells. With evidence increasing that other RTKs play a functional role in the nucleus, 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. We confirmed GrB as the protease that mediates cleavage and showed that GrB inhibition can block specific FGF-dependent effects on cancer cells. Having identified a functional role for nuclear FGFR1 in 2D and 3D 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. Thus we describe a novel mechanism by which FGF signalling can regulate cancer cell behaviour, and provide a novel potential target in treatment of invasive breast cancer.

The role of the stroma in cancer has come under increasing scrutiny over recent years 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. Abolishing FGFR1 and FGF2 function in PSCs leads to G1 cell-cycle block and a significant reduction in cell proliferation. In an organotypic model, nuclear FGFR1 and FGF2 were significantly greater in PSCs invading into the underlying stroma and, when treated with FGFR inhibitor, PSCs were unable to invade and FGFR1 and FGF2 remained cytoplasmic. Furthermore, effective blockade of nuclear FGFR1 signalling in PSCs abolished cancer cell invasion. Thus, preventing nuclear FGF/FGFR mediated proliferation in PSCs leads to disruption of the tumour microenvironment, preventing pancreatic cancer cell invasion.

Links:

Announcement from CCB home page

Centre for Cancer Biomedicine

Richard Grose's home page at BCI