pH and Ion Transport in Pancreatic Cancer

Informations projet

pHioniC

N° de convention de subvention: 813834

DOI

10.3030/813834

Projet clôturé

Date de signature de la CE 17 Août 2018

Date de début 1 Novembre 2018

Date de fin 30 Juin 2023

Financé au titre de

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coût total

€ 4 027 619,16

Contribution de l’UE

€ 4 027 619,16

Coordonné par

UNIVERSITAET MUENSTER
Germany

Periodic Reporting for period 2 - pHioniC (pH and Ion Transport in Pancreatic Cancer)

Période du rapport: 2020-11-01 au 2023-06-30

Résumé du contexte et des objectifs généraux du projet

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.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

Among others, the work has concentrated on (i) establishing models to study the impact of the characteristic pancreatic pH landscape, (ii) identifying pH-regulating and pH-regulated transport proteins involved in setting up and in responding to the unique pancreatic pH landscape, and (iii) to develop tools and concepts to exploit the pancreatic pH landscape therapeutically and/or diagnostically.
ad (i): Several new in vitro cell models and organoid preparations have been developed and new ex vivo preparations are currently optimized. Their common denominator is to mimic the characteristic properties of the PDAC microenvironment as closely as possible. This includes (the combination of) aciditiy, hypoxia, matrix composition and their mechanics as well as coculturing of tumor and stroma cells.
ad (ii): We identified a number of new ion channels whose expression and/or activities have previously not been studied in PDAC tumor and/or stroma cells. Moreover, we assessed their pH sensitivity and how this modifies their ability to regulate the aggressive cancer cell behavior such as cell proliferation, apoptosis or cell migration.
ad (iii): We explored the extracellular pancreatic pH landscape in in vitro and ex vivo preparations and identified the involved transport proteins. Moreover, we developed ADCs targeting a pH regulatory protein and ion channels strongly expressed in the acidic and hypoxic PDAC microenvironment.

At the end of the project we conclude that, by and large, we reached all of our main goals. Our results unequivocally reveal that the pancreatic pH landscape is a decisive player in PDAC pathophysiology. The transport proteins involved in generating this pH landscape as well as those sensing and transducing it to cell behavior bear great potential as targets for adjuvant therapy of PDAC. Their inhibition slows down PDAC progression. The relevance of the knowledge gained by the pHioniC project is illustrated by the fact that one of the pHioniC PIs has become co-founder of the company SOLID Therapeutics (https://www.solidtherapeutics.com). This company aims to therapeutically target the receptor for one of the metabolites that critically shapes the acidic tumor microenvironment.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

PDAC is the fourth most common cause of cancer-related death. The disease is almost always fatal and in contrast to many other cancer entities no efficient therapies are available. Thus, there is an urgent need to better understand the pathophysiology of this devastating disease. In our view it is the biggest progress of our project beyond the state-of-the-art to evaluate PDAC evolution and PDAC progression at the background of its host organ, the pancreas. The pancreas has a unique pH landscape and all results obtained so far indicate that pH has an important share in regulating PDAC tumor and stroma cell behavior. Therefore, this unique pH landscape has to be taken into account when designing new therapeutic concepts. The results of the pHioniC project clearly show that the consideration of the pancreatic pH landscape offers the potential for innovative therapeutic approaches. Importantly, these approaches can take advantage of repurposing drugs that have been employed in other medical disciplines. Their application as adjuvant therapeutics slows down PDAC progression in vitro and in vivo.

Pancreatic pH landscape during PDAC development