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

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 r...

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Bibliographic Details
Published in:Oncogenesis (New York, NY) Vol. 6; no. 7; p. e352
Main Authors: Rice, A J, Cortes, E, Lachowski, D, Cheung, B C H, Karim, S A, Morton, J P, del Río Hernández, A
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 03.07.2017
Nature Publishing Group
Subjects:
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Animal models
Apoptosis
Carcinoma
Cell Biology
Cell size
Cell survival
Chemoresistance
Chemotherapy
Drug resistance
E-cadherin
Extracellular matrix
Gemcitabine
Genetic engineering
Human Genetics
Internal Medicine
Intracellular signalling
Medicine
Medicine & Public Health
Mesenchyme
Oncology
Original
original-article
Paclitaxel
Pancreatic cancer
Rodents
Signal transduction
Survival
Tumor cell lines
Tumors
Vimentin
Yes-associated protein
β-catenin
ISSN:2157-9024, 2157-9024
Online Access:Get full text
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Summary: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.
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ISSN:2157-9024
2157-9024
DOI:10.1038/oncsis.2017.54