pH-Dependent Microenvironmental Ionic Signaling in Pancreatic Ductal Adenocarcinoma

Abstract

Aim: Pancreatic ductal adenocarcinoma (PDAC) develops within a uniquely dynamic pH landscape shaped by substantial acid-base fluxes produced by the exocrine pancreas. Secretion of alkaline pancreatic juice, normally linked to digestion, produces intermittent acidifications of the pancreatic interstitium, which challenges epithelial and stromal cells. It was postulated that these unique pancreatic pH dynamics can facilitate PDAC initiation and progression through selection of a more aggressive phenotype emerging with PDAC driver mutations.

Methods: Here, we summarize evidence that pH-regulatory transport proteins have an important role in shaping the PDAC microenvironment.

Results: pH-regulatory transport proteins generate and sense their microenvironment and act as signaling hubs to regulate proliferation, migration, and metabolism, and immune evasion. In this way, transport proteins that are crucial for the normal physiology of the exocrine pancreas are misused and become coerced into playing a pro-cancer role in pancreatic tumor cells, pancreatic stellate cells, or infiltrating immune cells. Experiments with PDAC mouse models revealed a therapeutic potential of targeting pH dynamics, notably by inhibition or genetic ablation of pH-regulatory proteins. It is a consistent finding that these maneuvers have a marked impact on the tumor immune defense and the communication between cancer and immune cells.

Conclusion: Collectively, we present a case for considering pH-regulating proteins as a therapeutic avenue.

FIGURE 1

Schematic representation of the mode of action of transport proteins in PDAC pathophysiology. The transportome is either expressed in the plasma membrane or in the membrane of intracellular organelles (transportome _i ). In addition to being the modifier of the microenvironment, the transportome is also the acceptor of the signals from the microenvironment and part of signal transduction pathways in cancer and stromal cells.

FIGURE 2

pH dynamics play a decisive role in PDAC pathophysiology and offer therapeutic opportunities. (A) Priming pancreatic cancer cells in the acidic tumor microenvironment profoundly alters their phenotype and promotes metastasis. (B–D) “pH‐targeting maneuvers” improve disease outcome in murine PDAC models. (B) Knockout or inhibition of NBCe1 (Slc4a4) improves tumor cell killing by activated T cells. (C.) NHE1 inhibition with cariporide reduces fibrosis and shifts the immune cell infiltrate from a neutrophilc to a lymphocytic one. (D) Combining gemcitabine with the carbonic anhydrase inhibitor reduces B cell infiltration into the tumor tissue. (This figure was created with Biorender.)