Analysis of Ephrin/Eph receptor signaling networks in lung cancer
Our aim is to evaluate and explore Ephrin and Eph signaling networks in lung cancer as novel therapeutic targets and biomarkers of response.
The current treatment regimens in lung cancer include a combination of chemotherapy and radiotherapy and for some cases targeted therapies against growth factor receptor signaling circuits. Ephrin ligands and their receptors Ephs, constitute signaling networks which are reported to influence proliferation and migration of tumor cells. Interestingly, global analyses of mutations in non-small cell lung cancer (NSCLC) have revealed Ephs to be among the top ten most frequently mutated genes. By defining the particular targets and signaling networks regulated by Ephrins and Ephs in lung cancer we aim to reveal if interference with these ligands and receptors can be used as novel therapeutic targets for this tumor malignancy.
By performing a total gene expression profiling of radiotherapy-resistant NSCLC cells after ionizing radiation or in combination with different PKC-inhibitors, we recently identified Ephrin B3 as a driver of radiotherapy resistance. We demonstrated a novel role of Ephrin B3 in NSCLC proliferation, cell death and radiotherapy sensitivity. By applying mass spectrometry methods and analyzing the phosphoproteome on a global scale we found that ablation of Ephrin B3 expression resulted in altered EphA2 phosphorylation, a receptor previously shown to drive tumor migration and invasiveness. Ongoing projects aim to understand if Ephrin B3 and its corresponding receptors drive NSCLC metastasis, but also to reveal the spatial distribution of Eph mutations in NSCLC of different histology.
Phosphoproteomic profiling of NSCLC cells reveals that ephrin B3 regulates pro-survival signaling through Akt1-mediated phosphorylation of the EphA2 receptor.
J. Proteome Res. 2011 May;10(5):2566-78
Inhibition of Ephrin B3-mediated survival signaling contributes to increased cell death response of non-small cell lung carcinoma cells after combined treatment with ionizing radiation and PKC 412.
Cell Death Dis 2013 Jan;4():e454