Periodic Reporting for period 1 - MechanoGPER (Development of GPER agonists as a novel therapeutic option for pancreatic cancer)
Periodo di rendicontazione: 2019-09-01 al 2021-02-28
Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is extremely aggressive and has very poor prognosis. It is characterised by a significant desmoplasia, immune-deficient response, and drug resistance. We discovered that targeting mechanosensory pathways mediated by G protein-coupled estrogen receptor (GPER) in pancreatic stellate cells (the main driver for the desmoplastic reaction) inhibits fibrosis. Using animal models, we also observed that GPER activation reduced the recruitment of tumour promoting macrophages to the tumour microenvironment. One of the most commonly used chemotherapies for PDAC is gemcitabine, but the effectiveness of this drug is hindered by the fact that pancreatic cancer cells rapidly develop chemoresistance. Using in vitro cellular models, we have discovered a molecular mechanism by which GPER activation reverts chemoresistance to gemcitabine. We are now validating this mechanism using mouse models. These results should open a new horizon for the future use of gemcitabine in PDAC patients. GPER is a relatively new discovered GPCR and controls mechanosensory pathways through the RhoA actomyosin contraction axis. This means that our observations may be applicable to other types of cells and cancer types.