Matrix stiffness induces epithelial-mesenchymal transition and promotes chemoresistance in pancreatic cancer cells

Rice, A.J., Cortes, E., Lachowski, D., Cheung, B.C.H., Karim, S.A., Morton, J.P. and Del Rio Hernandez, A. (2017) Matrix stiffness induces epithelial-mesenchymal transition and promotes chemoresistance in pancreatic cancer cells. Oncogenesis, 6(7), e352. (doi: 10.1038/oncsis.2017.54) (PMID:28671675) (PMCID:PMC5541706)

Abstract

Increased matrix rigidity associated with the fibrotic reaction is documented to stimulate intracellular signalling pathways that promote cancer cell survival and tumour growth. Pancreatic cancer is one of the stiffest of all human solid carcinomas and is characterised by a remarkable desmoplastic reaction. Here we use mouse models, genetically engineered to recapitulate human pancreatic cancer, and several pancreatic cancer cell lines as a model to investigate the effect of matrix stiffness in epithelial–mesenchymal transition (EMT) and resistance to chemotherapeutics. We found that recapitulation of the fibrotic rigidities found in pancreatic cancer tissues promote elements of EMT, including increases in vimentin expression, decreases in E-cadherin expression, nuclear localisation of β-catenin, YAP and TAZ and changes in cell shape towards a mesenchymal phenotype. We also report that stiffness induces chemoresistance to paclitaxel, but not to gemcitabine, both commonly used therapeutics, suggesting that environmental rigidity underlies an aspect of chemoresistance.

• Item Type: Articles
• Additional Information: This work was supported by the European Research Council (grant agreement 282051).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Morton, Professor Jen and Karim, Ms Saadia
• Authors: Rice, A.J., Cortes, E., Lachowski, D., Cheung, B.C.H., Karim, S.A., Morton, J.P., and Del Rio Hernandez, A.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Oncogenesis
• Publisher: Nature Publishing Group
• ISSN: 2157-9024
• ISSN (Online): 2157-9024
• Published Online: 03 July 2017
• Copyright Holders: Copyright © 2017 The Authors
• First Published: First published in Oncogenesis 6(7):e352
• Publisher Policy: Reproduced under a Creative Commons License