Interactions between K+ and H+ homeostasis in pancreatic cancer progression

• Applicant: Zoltan Pethö, Ph.D.
• Subject Area: Anatomy and Physiology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 546297112

This project aims to disrupt the local ion homeostasis in pancreatic ductal adenocarcinoma (PDAC) to attenuate tumor aggressiveness and strengthen chemotherapy effectiveness. I will focus on the interactions between K+ and H+ homeostasis, given the numerous functional connections of their respective transport proteins (“transportome”). The Na+/H+ exchanger 1 (NHE1), as well as multiple K+ channels, are overexpressed in tumor tissue from PDAC patients. Their contribution to PDAC progression has been shown in numerous preclinical models. Moreover, both NHE1 and K+ channels are phosphorylated and activated by downstream effectors of the KRAS pathway, which commonly has gain-of-function mutations in PDAC. I hypothesize that cation homeostasis is mechanistically strongly interlinked in PDAC progression. I will test the feasibility of transport protein modulation (in particular K+ channels and NHE1) for adjuvant chemotherapy. The study will evaluate the impact of the combined use of clinically tested and safe-to-use K+ channel modulators with the NHE1 inhibitor cariporide on PDAC through in vitro and in vivo models. In vitro screening on complex three-dimensional spheroid PDAC models will yield information regarding tumor growth, fibrosis, cell migration, viability, and anti-tumor immune response. Thereby, we will identify the most potent K+ channel activator(s) and inhibitor(s) to be combined with cariporide. Moreover, we will determine the molecular identity of critical players of the cation transportome in PDAC cells. We will underline the relevance of the elucidated proteins using human PDAC tissue samples and correlating spatial expression with patient prognosis. RNA sequencing (RNAseq), ionic and volume imaging, and neural network-based bioinformatical modeling will unravel downstream signaling pathways. The most promising combination treatment, together with the mutant KRAS inhibitor MRTX1133, will be tested in vivo in genetically engineered PDAC-bearing mice (KPfC). Here, this project aims to demonstrate to what extent and how such drugs affect tumor size, invasiveness, and fibrosis, and whether they affect tumor immune infiltration and chemotherapy efficacy. The effectiveness of the therapeutic modality will be evaluated based on tumor size, metastatic status, histopathological grade, scRNAseq, and immunohistochemistry. The knowledge of the complex interactions of the K+ and H+ homeostasis in PDAC will be used to propose an adjuvant treatment for pancreatic cancer by targeting the respective transport proteins.

• DFG Programme: Research Grants