Coetzee, A. S. et al. (2023) Nuclear FGFR1 promotes pancreatic stellate cell-driven invasion through up-regulation of Neuregulin 1. Oncogene, 42(7), pp. 419-500. (doi: 10.1038/s41388-022-02513-5) (PMID:36357571) (PMCID:PMC9918430)
![[img]](https://eprints.gla.ac.uk/style/images/fileicons/text.png) |
Text
286698.pdf - Published Version Available under License Creative Commons Attribution. 4MB |
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.
| Item Type: | Articles |
|---|---|
| Additional Information: | The authors thank the microscopy, bioinformatics and pathology core facilities at Barts Cancer Institute, funded by a Cancer Research UK core service grant (C16420/A18066). AC funded by a Pancreatic Cancer Research Fund project award, EC funded by CRUK and Barts Charity grants (A27781, G-002189), LF funded by a Breast Cancer Now project award (2017NovPR988), and SK and JM funded by CRUK grants (A25233, A29996). This work also supported by Cancer Research UK centre grants to the Beatson Institute (A17196, A31287) and Barts Cancer Institute (A25137). |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Morton, Professor Jen and Karim, Ms Saadia |
| Authors: | Coetzee, A. S., Carter, E. P., Rodríguez-Fernández, L., Heward, J., Wang, Q., Karim, S. A., Boughetane, L., Milton, C., Uyulur, F., Morton, J. P., Kocher, H. M., and Grose, R. P. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
| Journal Name: | Oncogene |
| Publisher: | Springer Nature |
| ISSN: | 0950-9232 |
| ISSN (Online): | 1476-5594 |
| Published Online: | 10 November 2022 |
| Copyright Holders: | Copyright © 2022 The Authors |
| First Published: | First published in Oncogene 42(7): 419-500 |
| Publisher Policy: | Reproduced under a Creative Commons License |
University Staff: Request a correction | Enlighten Editors: Update this record
Funder and Project Information
Funder and Project Information