Eph receptors and ephrins in cancer progression

Abstract

Evidence implicating Eph receptor tyrosine kinases and their ephrin ligands (that together make up the 'Eph system') in cancer development and progression has been accumulating since the discovery of the first Eph receptor approximately 35 years ago. Advances in the past decade and a half have considerably increased the understanding of Eph receptor-ephrin signalling mechanisms in cancer and have uncovered intriguing new roles in cancer progression and drug resistance. This Review focuses mainly on these more recent developments. I provide an update on the different mechanisms of Eph receptor-ephrin-mediated cell-cell communication and cell autonomous signalling, as well as on the interplay of the Eph system with other signalling systems. I further discuss recent advances in elucidating how the Eph system controls tumour expansion, invasiveness and metastasis, supports cancer stem cells, and drives therapy resistance. In addition to functioning within cancer cells, the Eph system also mediates the reciprocal communication between cancer cells and cells of the tumour microenvironment. The involvement of the Eph system in tumour angiogenesis is well established, but recent findings also demonstrate roles in immune cells, cancer-associated fibroblasts and the extracellular matrix. Lastly, I discuss strategies under evaluation for therapeutic targeting of Eph receptors-ephrins in cancer and conclude with an outlook on promising future research directions.

Figure 1.. Eph receptors and ephrins and their signaling mechanisms.

a. Family members and their domain structure. EphA receptors bind ephrin-As and EphB receptors bind ephrin-Bs, but EPHA4 can bind all ephrins and EPHB2 can bind EFNA5. *, capable of non-canonical signaling; **, lacking kinase activity. b. Bidirectional (forward and reverse) signaling is induced by Eph receptor–ephrin interaction in trans at intercellular junctions. It involves Eph receptor–ephrin dimerization and higher order oligomerization or clustering (event 1 in Box 1), Eph receptor and ephrin-B tyrosine phosphorylation, and binding of cytoplasmic effectors containing SH2, PDZ and other domains. c. Eph receptor–ephrin lateral cis interaction can inhibit binding in trans. Cis interactions can occur between Eph receptors and ephrins that do not interact in trans (bottom). d. Eph receptor ‘head-to-tail’ interaction involves low affinity binding of the ligand-binding domain to the second fibronectin type III domain. e. Non-canonical signaling involving phosphorylation of serine and threonine residues in the kinase–SAM linker of EPHA2, and also EPHA1 (see PhosphoSitePlus for details), is independent of ligand binding and receptor tyrosine kinase activity. f. Eph receptor phosphorylation by cytoplasmic or receptor tyrosine kinases (RTKs) leads to ephrin ligand-independent effects. g. Ephrin-B phosphorylation by RTKs leads to EphB receptor-independent effects. CK1, casein kinase 1; EGF, epidermal growth factor; FAK, focal adhesion kinase; GPI, glycosylphosphatidylinositol; PK, protein kinase; RSK, ribosomal S6 kinase.

Figure 2.. Eph receptor and ephrin mutations in tumors.

a. Percentage of tumors that harbor mutations in the indicated Eph receptor or ephrin. Dark blue indicates Eph receptor mutations co-occurring with other Eph receptor mutations and ephrin mutations co-occurring with other ephrin mutations. b. Eph receptor mutations recurring in 15 or more tumors. S, signal peptide; LBD, ligand-binding domain; Sushi, Sushi domain; EGF, epidermal growth factor-like domain; FNIII, fibronectin type III domain, T, transmembrane helix; kinase, kinase domain; SAM, SAM domain. c. Correlation between EPHA7 mutations and overall patient survival. d. Correlation between Eph receptor mutations and overall patient survival (note that tumors harboring EPHA7 mutations were excluded). e. Lack of significant correlation between ephrin mutations and overall patient survival. Data in this figure are from the curated set of non-redundant studies in cBioPortal, which as of June 2023 included 64,399 samples with mutation data. Kaplan-Meier survival curves in panels c, d, e compare patients with Eph receptor or ephrin mutant and nonmutant tumors. The relative median survival times in months, and p values according to the log-rank Mantel–Cox test, were obtained from the ‘Survival’ tab in cBioPortal.

Figure 3.. Therapeutic targeting of the Eph system in cancer.

Agents that have been used for therapeutic targeting of the Eph system in mouse preclinical studies and/or in clinical trials are indicated (agonists in light grey, various types of inhibitors in yellow, and chimeric antigen receptor (CAR)-modified T-cells in dark grey). Immunotherapies based on vaccines with Eph receptor peptides or CAR-dendritic cell vaccines are not shown. ‘Compound’ indicates either a small molecule or a larger chemical compound. MicroRNAs (miRs) and small interfering RNAs (siRNAs) can be delivered in vivo through liposomes to promote Eph receptor or ephrin mRNA cleavage or to repress mRNA translation. Histone deacetylase (HDAC) inhibitors can downregulate Eph receptor gene transcription by increasing acetylation of histones or transcription factors. Antibodies, peptides and recombinant ephrins have also been used to target drugs, radioactive substances, toxins and nanoparticles to Eph receptor- or ephrin-expressing tumor cells (not shown). sEPHB4-HSA, soluble EPHB4 ectodomain–human serum albumin.