Comprehensive modelling of multiple cell types reveals differences in Epo receptor signaling in primary erythroid and lung cancer cells

Lung cancer with its most prevalent form non-small-cell lung carcinoma (NSCLC) is one of the leading causes of cancer-related deaths worldwide and is commonly treated with chemotherapeutic drugs, e.g. cisplatin. Lung cancer patients frequently suffer from chemotherapy-induced anemia, which can be treated with erythropoietin (Epo). However, recent studies have indicated that Epo may not only induce erythropoiesis in hematopoietic cells but can also affect NSCLC cells.

We demonstrate that the NSCLC cell line H838 expresses functional EpoR and treatment with Epo reduces cisplatin-induced apoptosis. To pinpoint differences in Epo-induced signaling in erythroid progenitor cells (CFU-E, colony forming unit-erythroid) and H838 cells, we applied a computational approach to identify differences and commonalities in distinct cell systems by mathematical modeling in combination with an L1 penalization. By a simulation study, we demonstrate that this approach can accurately identify and quantify cell type-specific parameters. We then applied our strategy to quantitative time-resolved data of Epo-induced JAK/STAT signaling generated by quantitative immunoblotting, mass spectrometry and quantitative RT-PCR in CFU-E, H838 cells and H838 cells overexpressing the EpoR (H838-EpoR). A mathematical model could be established which comprehensively explain the data sets of H838, H838-EpoR and CFU-E cells and predicted nine differences between the CFU-E and H838 cells. Among them, the turnover rate of the mRNAs encoding the negative regulators SOCS3 and CIS could be validated experimentally by qRT-PCR for both cell types.

The systematic identification of pathway differences for EpoR signaling in cancer and hematopoietic cells promises to predict novel therapeutic strategies to selectively target tumor cells while leaving the healthy cells unaffected. The proposed modelling strategy could be employed as a general procedure to investigate cell-type specific signaling.

*Presenting author