pHioniC — pH and Ion Transport in Pancreatic Cancer

Results in brief

pH and Ion Transport in Pancreatic Cancer

pHioniC brings together highly synergistic expertise, research and training facilities to investigate pancreatic ductal adenocarcinoma (PDAC). PDAC is the fourth most common cause of cancer-related death. The disease is almost always fatal and its incidence is growing (with little difference between men and women) at a time when many other cancers are in decline. Although our knowledge of the genetics and epidemiology of PDAC is on par with other cancers, the molecular mechanisms that give rise to PDAC are far from clear and have not yet delivered targeted therapies. The program’s central hypothesis has a strong grounding in the organ physiology of the exocrine pancreas. Secretion of the alkaline pancreatic juice, normally associated with digestion, produces intermittent acidifications of the pancreas stroma resulting in an acid adaptation of pancreatic cells. We are first to propose that this adaptation facilitates PDAC initiation and progression by selecting for more aggressive phenotypes in interplay with PDAC driver mutations. An acidic microenvironment drives cancer progression by selecting aggressive cellular phenotypes e.g. with higher metastatic potential, but the underlying mechanisms are not clear. Early PDAC stages can be dormant for decades and some may not develop into full-blown disease. At this stage, acid selection of specific cancer phenotypes may trigger disease progression. A better understanding of the underlying pH-dependent mechanisms is required for designing innovative therapeutic concepts. Our research therefore aims to achieve the following main goals: (i) to map the pancreatic pH landscape and determine how it influences the onset and progression of disease in in vitro organoids and in animal models of PDAC in vivo; (ii) to dissect, using tractable cell/organoid models in vitro, the mechanisms by which pH influences the disease, and how the tumour shapes its pH landscape; (iii) to develop methods for modifying or exploiting pancreatic pH in a bid to influence the disease trajectory in the experimental and preclinical setting.

Data: CORDIS, © European Union

Project objective

pHioniC brings together highly synergistic expertise, research and training facilities to investigate pancreatic ductal adenocarcinoma (PDAC), a frequent and aggressive cancer that is still incurable. The programme’s central hypothesis has a strong grounding in the physiology of the exocrine pancreas. Secretion of the alkaline pancreatic juice, normally associated with digestion, leads to acidifications of the pancreas stroma resulting in an acid adaptation of pancreatic cells. We are first to propose that this adaptation facilitates PDAC initiation and progression by selecting for more aggressive phenotypes in interplay with PDAC driver mutations. pHioniC will:(i) develop models (e.g. pancreas-/PDAC-specific pH-indicator mouse) to map the pH landscape in the normal and diseased pancreas,(ii) characterize the impact of the acidic microenvironment in PDAC development and(iii) design bespoke approaches to the treatment of PDAC that exploit the unique physiology of the pancreas and utilize a combination of nanocarrier and antibody technology for targeting.Thereby, pHioniC provides an innovative interdisciplinary and intersectoral training for ESRs at the forefront of oncological research. pHioniC comprises excellent complementary basic-research, clinical, and in silico laboratories that provided the seed discoveries for this novel concept, and industrial partners with a track record in therapeutic and diagnostic development in oncology. This highly synergistic team combines the state-of-the-art research tools and translational opportunities needed to meet the most ambitious doctoral programmes. pHioniC training for ESRs covers the fields of ion transport, oncology, imaging, bioinformatics and antibody technology, and is complemented by extensive transferable skills and personalised training elements. pHioniC will establish a lasting contribution towards European doctoral training beyond the lifetime of the project.

Original text from CORDIS.

Participants

UNIVERSITAET MUENSTER · MuensterCoordinatorGermany
CHRISTIAN-ALBRECHTS-UNIVERSITAET ZU KIEL · KielGermany
DEBRECENI EGYETEM · DebrecenHungary
ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM · RotterdamNetherlands
GEORG-AUGUST-UNIVERSITAT GOTTINGEN STIFTUNG OFFENTLICHEN RECHTS · GottingenGermany
HEIDELBERG PHARMA RESEARCH GMBH · LADENBURGGermany
KOBENHAVNS UNIVERSITET · KOBENHAVNDenmark
MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV · MUNCHENGermany
PERCUROS BV · 's-Gravenhage (Den Haag)Netherlands
THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD · OxfordUnited Kingdom
TYPEONE S.R.L. · LecceItaly
UNIVERSITA DEGLI STUDI DI BARI ALDO MORO · BariItaly
UNIVERSITA DEGLI STUDI DI FIRENZE · FlorenceItaly
UNIVERSITA DEGLI STUDI DI PADOVA · PadovaItaly
UNIVERSITA DEGLI STUDI DI TORINO · TorinoItaly
UNIVERSITE DE LILLE · LilleFrance
UNIVERSITE DE PICARDIE JULES VERNE · AmiensFrance

pHioniC · pH and Ion Transport in Pancreatic Cancer

Results in brief

pH and Ion Transport in Pancreatic Cancer

Project objective

Participants

Links