PDA_TGFb · TGF-beta mediated crosstalk between cancer (stem) cells and tumor microenvironment in pancreatic cancer metastasis
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2017-02-12 → 2019-07-13
- EU contribution
- €180,277
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
TGF-beta mediated crosstalk between cancer (stem) cells and tumor microenvironment in pancreatic cancer metastasis
Pancreatic ductal adenocarcinoma (PDAC) is the fourth-leading cause of cancer-related death in the world, with a 5-year survival rate of less than 5%. Chemotherapy resistance and tumour relapse are two unresolved problems in PDAC treatment. Cancer stem cells (CSCs) are key drivers in tumour progression, resistance and relapse and studying CSC biology may provide novel insights that could help to overcome these problems. Indeed, up-regulation of detoxifying enzymes and drug transporters in pancreatic CSCs have already been identified as important mechanisms for chemo-resistance in PDAC. Hence, targeting the CSC niche and their plasticity could be a complementary therapeutic strategy against cancer. Transforming growth factor beta (TGF-β) signalling is one of the most important pathways supporting the CSC niche and plasticity in PDAC. High levels of TGF-β1 in patients with PDAC are associated with poor prognosis in the clinical setting. It has been reported that the pancreatic stellate cells (PSC) within the tumour microenvironment represent the principal source of TGF-β1, but very little is known about the TGF-β1 mediated crosstalk between PSC and PDAC cells. The main goal of this project was to increase survival of pancreatic cancer patients by exploring the contribution of the tumour microenvironment to the failure of presently available oncological treatments. Specifically, we aimed to: 1) Obtain pure subpopulations from epithelium and stroma of PDAC human samples; 2) Define the role of TGFB_SLs and the signaling pathways activated during the tumor-stroma crosstalk; and 3) Determine whether the metastatic cells activate the TGFB_SLs-driven stromal response at the metastatic site.
Data: CORDIS, © European Union
Project objective
More than 50% of all pancreatic cancer patients suffer of metastasis either at the time of diagnosis or as recurrent disease after therapy. During metastatic dissemination, cancer (stem) cells shed into the blood stream and seed the liver as isolated entities. Genetic alterations underlying these processes have not been identified thus far. Therefore, it is currently not possible to discriminate which patients are at higher risk of developing metastasis or to design targeted therapies to prevent this process. Interestingly, a broad subset of pancreatic cancers (PDAs) are characterized by high TGF-beta superfamily ligands (TGFB_SLs) levels (TGFβ1, Nodal and Activin) and by prominent TGF-beta signaling in tumor stromal cells. The main goal of this project is to unravel how the microenvironment of the primary tumor helps tumor cells to colonize a distant organ. Specifically, PDA_TGFB aims to: 1) Identify and characterize the cancer (stem) cells and stromal cells involved in the crosstalk responsible of the tumor progression; 2) Define the role of TGFB_SLs during the tumor-stroma crosstalk and Identify the signaling pathways involved in the crosstalk; 3) Determine whether the metastatic cells activate the TGFB_SLs-driven stromal response at the metastatic site. By using a multidisciplinary approach that includes the use of cell culture models and animal models, in which TGF-beta signaling (and/or target genes) is selectively induced or abolished, we expect to identify additional factors involved in the metastatic process as well as to identify ways to interfere with the metastatic niche within the liver. Overall, this study will clarify the role of TGF-beta signaling in the metastatic process, thus opening novel avenues for the development of diagnostic and therapeutic strategies for PDA.
Original text from CORDIS.
Participants
- CONSIGLIO NAZIONALE DELLE RICERCHE · RomaCoordinatorItaly
Links
Data: CORDIS, © European Union