Metastasis, the spread of cancer cells from the primary tumour to a secondary site, requires biochemical and physical changes in cellular behaviour that are influenced by the tumour microenvironment. In pancreatic ductal adenocarcinoma (PDAC), excessive deposition of extracellular matrix proteins leading to increased stiffness characteristically occurs with cancer development, and the fibrotic stroma produced promotes tumourigenesis. Many cellular behaviours, for example the epithelial-mesenchymal transition (EMT), chemoresistance and invasiveness, are associated with increased levels of metastasis. Furthermore, cell mechanics and physical processes such as force generation and mechanosensing are linked to invasion, and inhibition of these processes is an important therapeutic avenue of research.
In this work, we describe how extracellular matrix stiffness can promote EMT and chemoresistance to paclitaxel in pancreatic cancer cells. We analysed the rigidity of mouse pancreatic tissue, both healthy and PDAC, and then cultured multiple pancreatic cancer cell lines on gels of tunable rigidity to recapitulate the various stiffness values observed. We then used immunofluorescence and cell viability assays to determine the role of rigidity on EMT and chemoresistance.
We target cell mechanics in pancreatic cancer cells and demonstrate that the G protein-coupled estrogen receptor (GPER) influences pancreatic cancer cell mechanics to reduce invasion, cell contractility, mechanosensing, stiffness, and EMT. We find that GPER is downregulated in cancer patients and that its activation by a specific agonist, as well as the breast cancer drug tamoxifen, affects pancreatic cell mechanics and reduces invasion through a physiologically relevant basement membrane mimic. Cell mechanics in prostate cancer cells are similarly affected by GPER activation, indicating the wide-ranging potential of GPER as a therapeutic target.
These results demonstrate the importance of cell mechanics and the metastatic processes of EMT, chemoresistance, and invasion, and how the targeting of these by GPER activation may offer a potential therapeutic route.