title: Identification of Cell Type-Specific Differences in Erythropoietin Receptor Signaling in Primary Erythroid and Lung Cancer Cells.
abstract: 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 such as cisplatin. Lung cancer patients frequently suffer from chemotherapy-induced anemia, which can be treated with erythropoietin (EPO). However, studies have indicated that EPO not only promotes erythropoiesis in hematopoietic cells, but may also enhance survival of NSCLC cells. Here, we verified that the NSCLC cell line H838 expresses functional erythropoietin receptors (EPOR) and that treatment with EPO reduces cisplatin-induced apoptosis. To pinpoint differences in EPO-induced survival signaling in erythroid progenitor cells (CFU-E, colony forming unit-erythroid) and H838 cells, we combined mathematical modeling with a method for feature selection, the L1 regularization. Utilizing an example model and simulated data, we demonstrated that this approach enables the accurate identification and quantification of cell type-specific parameters. We applied our strategy to quantitative time-resolved data of EPO-induced JAK/STAT signaling generated by quantitative immunoblotting, mass spectrometry and quantitative real-time PCR (qRT-PCR) in CFU-E and H838 cells as well as H838 cells overexpressing human EPOR (H838-HA-hEPOR). The established parsimonious mathematical model was able to simultaneously describe the data sets of CFU-E, H838 and H838-HA-hEPOR cells. Seven cell type-specific parameters were identified that included for example parameters for nuclear translocation of STAT5 and target gene induction. Cell type-specific differences in target gene induction were experimentally validated by qRT-PCR experiments. The systematic identification of pathway differences and sensitivities of EPOR signaling in CFU-E and H838 cells revealed potential targets for intervention to selectively inhibit EPO-induced signaling in the tumor cells but leave the responses in erythroid progenitor cells unaffected. Thus, the proposed modeling strategy can be employed as a general procedure to identify cell type-specific parameters and to recommend treatment strategies for the selective targeting of specific cell types.
authors: Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), INF 280, Heidelberg, Germany.|Translational Lung Research Center (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.
authors: Ruth
authors: R
authors: Merkle
authors: Institute of Physics, University of Freiburg, Germany & BIOSS Centre for Biological Signalling Studies, University of Freiburg, Germany.
authors: Bernhard
authors: B
authors: Steiert
authors: Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), INF 280, Heidelberg, Germany.|Translational Lung Research Center (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.
authors: Florian
authors: F
authors: Salopiata
authors: Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), INF 280, Heidelberg, Germany.|Translational Lung Research Center (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.
authors: Sofia
authors: S
authors: Depner
authors: Institute of Physics, University of Freiburg, Germany & BIOSS Centre for Biological Signalling Studies, University of Freiburg, Germany.
authors: Andreas
authors: 0000-0002-9198-2489
authors: A
authors: Raue
authors: Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), INF 280, Heidelberg, Germany.
authors: Nao
authors: 0000-0003-3362-375X
authors: N
authors: Iwamoto
authors: Institute of Physics, University of Freiburg, Germany & BIOSS Centre for Biological Signalling Studies, University of Freiburg, Germany.
authors: Max
authors: 0000-0002-3723-5722
authors: M
authors: Schelker
authors: Institute of Physics, University of Freiburg, Germany & BIOSS Centre for Biological Signalling Studies, University of Freiburg, Germany.
authors: Helge
authors: 0000-0003-0577-2432
authors: H
authors: Hass
authors: Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), INF 280, Heidelberg, Germany.|Translational Lung Research Center (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.
authors: Marvin
authors: M
authors: Wäsch
authors: Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), INF 280, Heidelberg, Germany.
authors: Martin E
authors: ME
authors: Böhm
authors: Division Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), INF 280, Heidelberg, Germany.
authors: Oliver
authors: O
authors: Mücke
authors: Regulation of Cellular Differentiation Group, Division Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), INF 280, Heidelberg, Germany.
authors: Daniel B
authors: 0000-0001-5081-7869
authors: DB
authors: Lipka
authors: Division Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), INF 280, Heidelberg, Germany.
authors: Christoph
authors: C
authors: Plass
authors: Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), INF 280, Heidelberg, Germany.
authors: Wolf D
authors: WD
authors: Lehmann
authors: Institute of Physics, University of Freiburg, Germany & BIOSS Centre for Biological Signalling Studies, University of Freiburg, Germany.
authors: Clemens
authors: C
authors: Kreutz
authors: Institute of Physics, University of Freiburg, Germany & BIOSS Centre for Biological Signalling Studies, University of Freiburg, Germany.
authors: Jens
authors: J
authors: Timmer
authors: Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), INF 280, Heidelberg, Germany.
authors: Marcel
authors: 0000-0002-9517-5166
authors: M
authors: Schilling
authors: Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), INF 280, Heidelberg, Germany.|Translational Lung Research Center (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.
authors: Ursula
authors: U
authors: Klingmüller
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019295:Computational Biology; D041905:Erythroid Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D017467:Receptors, Erythropoietin / Q000032:analysis / Q000145:classification / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D017467:Receptors, Erythropoietin