The EPH/Ephrin System in Pancreatic Ductal Adenocarcinoma (PDAC): From Pathogenesis to Treatment

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a major concern for health care systems worldwide, since its mortality remains unaltered despite the surge in cutting-edge science. The EPH/ephrin signaling system was first investigated in the 1980s. EPH/ephrins have been shown to exert bidirectional signaling and cell-to-cell communication, influencing cellular morphology, adhesion, migration and invasion. Recent studies have highlighted the critical role of the EPH/ephrin system in various physiologic processes, including cellular proliferation, survival, synaptic plasticity and angiogenesis. Thus, it has become evident that the EPH/ephrin signaling system may have compelling effects on cell homeostasis that contribute to carcinogenesis. In particular, the EPH/ephrins have an impact on pancreatic morphogenesis and development, whereas several EPHs and ephrins are altered in PDAC. Several clinical and preclinical studies have attempted to elucidate the effects of the EPH/ephrin pathway, with multilayered effects on PDAC development. These studies have highlighted its highly promising role in the diagnosis, prognosis and therapeutic management of PDAC. The aim of this review is to explore the obscure aspects of the EPH/ephrin system concerning the development, physiology and homeostasis of the pancreas.

Keywords: EPH/eprin; PDAC; immunotherapy; pancreatic cancer; signaling pathway.

Figure 1

Basic molecular structure of the EPH/ephrin signaling compartment. In the plasma membrane, ephrin-A ligands are hooked by a glycosylphosphatidylinositol (GPI) anchor, although they can also activate distant EPH receptors. On the other hand, ephrin-B ligands contain a transmembrane domain and a cytoplasmic segment. EPHs/ephrin interaction results in the beginning of a molecular series of events. Forward signaling is triggered by EPH–ephrin binding as well as through EPH interplay with various biomolecules and signaling pathways. Reverse signaling is stimulated by the EPHs in the ephrin-expressing cells. Cis-signaling is the interaction of EPHs and ephrins with molecules on the same cell membrane. Proteins that encompass Src Homology 2 (SH2) or PDZ domains participate in the transmission of the downstream signal through their interaction with ephrins. Created with BioRender.com.

Figure 2

Basic mechanisms influenced by the EPH/ephrin system: (A) RT, EPHA2 and EPHB4/ephrin-B2 shape the immune cellular population of TME. (B) EPHA2/ephrin-A1 influences the metastatic potential of cancer cells. (C) Ephrin-B2 regulates G0/G1 cell cycle transition. (D) EPHA2/ephrin-A1 induce tumor growth. Created with BioRender.com.