Emerging evidence suggests pleiotropic functions of death receptors TRAIL-R1 and TRAIL-R2 in the biology of PDAC.In their canonical localization at the plasma membrane, TRAIL-R1/-R2 may induce cell death and/or pro-inflammatory signaling leading to cell migration, invasion and metastasis. Two other TRAIL receptors, TRAIL-R3 and TRAIL-R4 negatively regulate TRAIL-induced apoptosis by binding to TRAIL-R1/R2 and competing for the ligand. Recent discoveries suggest also important, yet still not fully understood cancer-relevant functions of intracellular TRAIL receptors. Thus, cytoplasmic TRAIL-R1/-R2 play a role in ER stress response, whereas nuclear TRAIL-R2 inhibits maturation of miRNA let-7 thereby promoting cell proliferation, tumor growth, EMT and metastasis. The function of intracellular TRAIL-R3/-R4 is not known.

Our unpublished data show that TRAIL-Rs differentially regulate the expression pH regulatory (transport) proteins pointing to their involvement in “pH sensing”. Our project aims:  i) To elucidate the impact of changes of extracellular pH on the intracellular distribution and plasma membrane- as well as nuclear functions of TRAIL receptors. ii) To understand the role of individual TRAIL receptors (death receptors TRAIL-R1 /-R2; decoy receptor TRAIL-R4) in intracellular pH control in PDAC cells.