Periodic Reporting for period 1 - UNBRACE (Investigating the Role of the Unfolded Protein Response as a Novel Targetable Pathway in BRAF Mutant Colorectal Cancer)
Okres sprawozdawczy: 2019-02-01 do 2021-01-31
Pancreatic ductal adenocarcinoma (PDAC) accounts for approximately 90% of all cases of pancreatic cancer. Pancreatic stellate cells (PSCs) are the most prominent cell type in the PDAC stroma, accounting for around 50% of the tumour microenvironment. Interestingly, PSCs show chronic cellular stress as seen by the persistent activity of the unfolded protein response (UPR). The UPR is a cellular pathway that is triggered by the accumulation of misfolded proteins in the endoplasmic reticulum (ER), a condition known as ER stress. The UPR is normally a transient adaptive response mechanism that aims at resolving the ER stress and returning the cell to an unstressed state. However, when it is persistently active in cancer, the UPR can promote tumour growth and progression. Modulating UPR signalling using small molecule inhibitors is therefore an attractive approach for intervention in pancreatic cancer. The overall aim of this project was to understand the role the UPR in cancer and to develop novel compounds that can switch it off. This was addressed through two objectives; (a) investigation into the role of UPR in PDAC and its tumour microenvironment, and (b) develop tools to test novel small molecule inhibitors to target the UPR in these cells. These scientific aims were underpinned by the cross-cutting objectives of training and transfer of knowledge between the fellow and the host organisation. Thus the fellow gained training from the expertise of the host in UPR biology and cancer, and integrated it with his own expertise in immune cells and inflammatory responses.
Conclusions of the action: Through the course of the UNBRACE project we were able to understand possible roles for UPR in the PDAC and the associated TME. We have further developed tools to test small molecule inhibitors to target the UPR as a potential future therapeutic target. The extrapolation of the undergone work will hypothetically delineate impactful publications, and tools to develop cancer therapeutics.
Conclusions of the action: Through the course of the UNBRACE project we were able to understand possible roles for UPR in the PDAC and the associated TME. We have further developed tools to test small molecule inhibitors to target the UPR as a potential future therapeutic target. The extrapolation of the undergone work will hypothetically delineate impactful publications, and tools to develop cancer therapeutics.
During the project we showed that there is persistent activity of the UPR in PDAC and PSC cell lines, and that the UPR can shape the tumour microenvironment thus affecting aspects of cancer development. We further showed that inhibition of the UPR in these cells can affect the tumour microenvironment by altering communication between PDAC and PSC cells via an altered profile of secreted factors released from both cell types. In addition, we developed two high-throughput cell-based assays for UPR activity that can be used to test novel molecules that inhibit the UPR. The results regarding the role of the UPR in shaping the tumour microenvironment were disseminated in seminar presentations given at NUI Galway. The host organisation is continuing to work on this project and plans to publish the data in a peer-reviewed journal when the story is complete. Any intellectual property will be protected.
Through the course of the UNBRACE project, we were able to understand possible roles for UPR in the PDAC and the associated TME. We have further developed tools to test small molecule inhibitors to target the UPR as a potential future therapeutic target. The extrapolation of the undergone work will hypothetically delineate impactful publications and tools to develop cancer therapeutics.