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

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.

FAK controls the mechanical activation of YAP, a transcriptional regulator required for durotaxis

“…Fibronectin‐coated polyacrylamide gels were used to culture cells; the substrate stiffness could be altered by changing the acrylamide/bisacrylamide ratio without affecting the surface composition (8, 23, 24). We observed a significant increase in YAP nuclear localization in wildtype HSCs with increasing rigidity (from 4 to 25 kPa) ( Fig .…”

“…Phosphorylation of YAP on Ser 127 by a wide variety of kinases, including CDK1 and PI3K, inactivates it and prevents it from translocating to the nucleus, where it would interact with transcription factors to promote the expression of genes associated with the cell cycle and proliferation (6, 7). Localization of activated YAP to the nucleus and up‐regulation of multiple YAP‐dependent genes have been shown to be sensitive to substrate stiffness (5, 8) as well as other mechanical cues such as cyclic stretching, requiring Rho and a functional actin cytoskeleton (5). Furthermore, YAP activation has been shown to promote cell migration of breast cancer cells (9).…”

Optical study of chemotherapy efficiency in cancer treatment via intracellular structural disorder analysis using partial wave spectroscopy

“…The over expression of P‐glycoprotein and other ion channels in the chemoresistant cells alter the ionic efflux and influx from inside and outside of the cell . The altered ionic balance and variation in cell volume , contribute to the variation of characteristic attributes which affects the matrix stiffness and cell texture in chemoresistant cells in comparison to the control cells . All these changes within chemoresistant cells enhances the randomness/disorderness, resulting in disabling of the cellular integrity .…”

Tamoxifen mechanically reprograms the tumor microenvironment via HIF ‐1A and reduces cancer cell survival

“…In order to gain insights in the mechanism by which tamoxifen decreases LOX-L2 levels in PSCs, we cultured these cells in polyacrylamide (PAA) matrices of varying rigidities: 1 kPa (soft matrix) or 25 kPa (stiff matrix) as previously reported [25,26]. LOX-L2 and HIF-1A levels were significantly upregulated in PSCs cultured on stiff compared to the soft matrices, and tamoxifen-treated PSCs cultured on stiff substrates expressed LOX-L2 and HIF-1A levels comparable to the ones shown on the soft matrices ( Fig 2H).…”