Nuclear FGFR1 promotes pancreatic stellate cell-driven invasion through up-regulation of Neuregulin 1

Abstract

Pancreatic stellate cells (PSCs) are key to the treatment-refractory desmoplastic phenotype of pancreatic ductal adenocarcinoma (PDAC) and have received considerable attention as a stromal target for cancer therapy. This approach demands detailed understanding of their pro- and anti-tumourigenic effects. Interrogating PSC-cancer cell interactions in 3D models, we identified nuclear FGFR1 as critical for PSC-led invasion of cancer cells. ChIP-seq analysis of FGFR1 in PSCs revealed a number of FGFR1 interaction sites within the genome, notably NRG1, which encodes the ERBB ligand Neuregulin. We show that nuclear FGFR1 regulates transcription of NRG1, which in turn acts in autocrine fashion through an ERBB2/4 heterodimer to promote invasion. In support of this, recombinant NRG1 in 3D model systems rescued the loss of invasion incurred by FGFR inhibition. In vivo we demonstrate that, while FGFR inhibition does not affect the growth of pancreatic tumours in mice, local invasion into the pancreas is reduced. Thus, FGFR and NRG1 may present new stromal targets for PDAC therapy.

MET exon 14 skipping mutation is a hepatocyte growth factor (HGF)‐dependent oncogenic driver in vitro and in humanised HGF knock‐in mice

“…A protocol modified from [ 42 ] was used. Spheres were formed in 2.5% (v/v) methylcellulose 4000 cP (Sigma‐Aldrich, Saint‐Louis, MO, USA) hanging droplets using 1000 cells total in a 2 : 1 ratio MRC5 fibroblasts: 16HBE‐WT or ‐ex14 cells.…”

Arachidonate 15-lipoxygenase-mediated production of Resolvin D5n-3 DPA abrogates pancreatic stellate cell-induced cancer cell invasion

“…Prior to spheroid generation, PS1 cells were pre-treated for 7 days. 3D spheroid cancer cell/PS1 co-cultures were generated using a hanging drop spheroid model developed by Ed Carter/Richard Grose (BCI-QMUL), based on previous work ( 40 ) ( Supplementary Methods ).…”

“…Previously described ( 7 , 8 , 40 ), well-established techniques were used ( Supplementary Methods ).…”

Single-nucleus RNA sequencing reveals heterogenous microenvironments and specific drug response between cervical squamous cell carcinoma and adenocarcinoma

“… 80 The transcription levels of NRG1 act in an autocrine fashion through an ERBB2/4 heterodimer to promote the invasion of pancreatic stellate cells. 81 Integrin, as a key transmembrane receptor, has been proven to play key roles in the development and carcinogenesis of malignant tumors by regulating MAPK or STAT5. 67 , 68 , 82 Consistent with the results of cellular communications, some specifically sensitive chemotherapy drugs targeting ERBB2 and MAPK/STAT5 were identified for CAde and CSCC, respectively.…”