Research

Our main research interest is to understand how molecular networks within cells — such as signal transduction cascades and gene regulatory networks — process information and how these networks dysfunction in disease.

Our group combines mathematics, bioinformatics, quantitative biology and single cell methods to investigate how structure and dynamics of networks relate to their biological function. Specifically, the main research aim of the group is to understand how oncogenic signaling pathways and their downstream gene regulatory networks mediate their oncogenic potential, how drugs can effectively modulate these networks and how resistance against targeted kinase inhibitors arises.

We work in close interplay between experiments, theory and computation.

Some of the key questions we are interested in are:

• What are the specific phenotypes driven by oncogeneic mutations? (see e.g. Hollek et al, 2026)
• How do cells discriminate between short and long signals? Why do chronic signals (such as induced by oncogenes) trigger other transcriptional programmes than transient signals? (see e.g. Uhlitz et al, 2017).
• What is the role of ubiquitiously found feedbacks in signalling? What are the consequences of these fedbacks for targeted inhibitors (see e.g. Klinger et al, 2013 and Fritsche-Guenther et al, 2011).
• The dose of proteins varyies strongly between individual clonal cells. How can cells deal with it? What are the mechanisms that control protein dose? (Schmiedel et al, 2015, Fritsche-Guenter et al, 2011)

To address these questions, we generate quantitative or genome-wide experimental data. We analyse and integrate these data using state-of-the-art bioinformatical methods and mathematical models.

Key publications

1. Hollek, V.; Böhning, F.; Florez Vargas, C.; Sieber, A.; Morkel, M. and Blüthgen, N.
   Pooled single-cell screen in colorectal cancer defines transcriptional modules linked to oncogenes.
   Molecular systems biology, 22: 435-460, 2026. doi  pubmed 
2. van Bentum, M.; Klinger, B.; Sieber, A.; Naghiloo, S.; Zauber, H.; Lehmann, N.; Haji, M.; Niquet, S.; Mertins, P.; Blüthgen, N. * and Selbach, M. *
   Spike-in enhanced phosphoproteomics uncovers synergistic signaling responses to MEK inhibition in colon cancer cells.
   Nature communications, 16 (1): 4884, 2025. doi 
3. Steinbrecht, D. *; Minia, I. *; Milek, M.; Meisig, J.; Blüthgen, N. * and Landthaler, M. *
   Subcellular mRNA kinetic modeling reveals nuclear retention as rate-limiting.
   Molecular Systems Biology, 20 (12): 1346—1371, 2024. doi  pubmed 
4. Peidli, S. *; Green, T. D. *; Shen, C.; Gross, T.; Min, J.; Garda, S.; Yuan, Bo; Schumacher, L. J.; Taylor-King, J. P.; Marks, D. S.; Luna, A. *; Blüthgen, N. * and Sander, C. *
   scPerturb: harmonized single-cell perturbation data.
   Nature Methods, 2024. doi 
5. Sell, T.; Klotz, C.; Fischer, M. M.; Astaburuaga-García, R.; Krug, S.; Drost, J.; Clevers, H.; Sers, C.; Morkel, M. and Blüthgen, N.
   Oncogenic signaling is coupled to colorectal cancer cell differentiation state.
   Journal of Cell Biology, 222 (6), 2023. doi 
6. Georg, P. *; Astaburuaga-Garcia, R. *; Bonaguro, L. *; Brumhard, S.; Michalick, L.; Lippert, L. J.; Kostevc, T.; Gäbel, C.; Schneider, M.; Streitz, M.; Demichev, V.; Gemünd, I.; Barone, M.; Tober-Lau, P.; Helbig, E. T.; Hillus, D.; Petrov, L.; Stein, J.; Dey, H-P.; Paclik, D.; Iwert, C.; Mülleder, M.; Aulakh, S. K.; Djudjaj, S.; Bülow, R. D.; Mei, H. E.; Schulz, A. R.; Thiel, A.; Hippenstiel, S.; Saliba, A-E.; Eils, R.; Lehmann, I.; Mall, M. A.; Stricker, S.; Röhmel, J.; Corman, V. M.; Beule, D.; Wyler, E.; Landthaler, M.; Obermayer, B.; von Stillfried, S.; Boor, P.; Demir, M.; Wesselmann, H.; Suttorp, N.; Uhrig, A.; Müller-Redetzky, H.; Nattermann, J.; Kuebler, W. M.; Meisel, C.; Ralser, M.; Schultze, J. L.; Aschenbrenner, A. C.; Thibeault, C.; Kurth, F.; Sander, L. E. *; Blüthgen, N. * and Sawitzki, B. *
   Complement activation induces excessive T cell cytotoxicity in severe COVID-19.
   Cell, 185: 493-512, 2022. doi 
7. Dorel, M; Klinger, B; Mari, T; Toedling, J; Blanc, E; Messerschmidt, C; Nadler-Holly, M; Ziehm, M; Sieber, A; Hertwig, F; Beule, D; Eggert, A; Schulte, J H; Selbach, M and Blüthgen, N
   Neuroblastoma signalling models unveil combination therapies targeting feedback-mediated resistance.
   PLoS Comput Biol, 17: e1009515, 2021. doi  pubmed 
8. Bischoff, P; Trinks, A; Obermayer, B; Pett, JP; Wiederspahn, J; Uhlitz, F; Liang, X; Lehmann, A; Jurmeister, P; Elsner, A; Dziodzio, T; Rückert, JC; Neudecker, J; Falk, C; Beule, D; Sers, C; Morkel, M; Horst, D; Blüthgen, N * and Klauschen, F *
   Single-cell RNA sequencing reveals distinct tumor microenvironmental patterns in lung adenocarcinoma.
   Oncogene, 40: 6748-6758, 2021. doi  pubmed 
9. Uhlitz, F *; Bischoff, P *; Peidli, S *; Sieber, A; Trinks, A; Lüthen, M; Obermayer, B; Blanc, E; Ruchiy, Y; Sell, T; Mamlouk, S; Arsie, R; Wei, T T; Klotz-Noack, K; Schwarz, R F; Sawitzki, B; Kamphues, C; Beule, D; Landthaler, M; Sers, C; Horst, D; Blüthgen, N * and Morkel, M *
   Mitogen-activated protein kinase activity drives cell trajectories in colorectal cancer.
   EMBO Mol Med., 13: e14123, 2021. doi  pubmed 
10. Meisig, J.; Dreser, N.; Kapitza, M.; Henry, M.; Rotshteyn, T.; Rahnenführer, J.; Hengstler, J. G.; Sachinidis, A.; Waldmann, T.; Leist, M. and Blüthgen, N.
    Kinetic modeling of stem cell transcriptome dynamics to identify regulatory modules of normal and disturbed neuroectodermal differentiation.
    Nucleic Acids Res: 12577-12592, 2020. doi  pubmed 
11. Gross, T. and Blüthgen, N.
    Identifiability and experimental design in perturbation studies.
    Bioinformatics, 36: i482-i489, 2020. pubmed 
12. Rydenfelt, M. *; Klinger, B. *; Klünemann, M. and Blüthgen, N.
    SPEED2: inferring upstream pathway activity from differential gene expression.
    Nucleic Acids Research, 48: W307-W312, 2020. doi 
13. Benary, M. *; Bohn, S. *,; Lüthen, M.; Nolis, I.; Blüthgen, N. * and Loewer, A. *
    Disentangling pro-mitotic signaling during cell cycle progression using time-resolved single-cell imaging.
    Cell reports, 31: 107514, 2020. doi 
14. Brandt, R. *; Sell, T. *; Lüthen, M.; Uhlitz, F.; Klinger, B.; Riemer, P.; Giesecke-Thiel, C.; Schulze, S.; El-Shimy, I. A.; Kunkel, D.; Fauler, B.; Mielke, T.; Mages, N.; Herrmann, B. G; Sers, C.; Blüthgen, N. * and Morkel, M. *
    Cell type-dependent differential activation of ERK by oncogenic KRAS in colon cancer and intestinal epithelium.
    Nature communications, 10 (1): 2919, 2019. doi 
15. Bischoff, P; Trinks, A; Wiederspahn, J; Obermayer, B; Pett, JP; Jurmeister, P; Elsner, A; Dziodzio, T; Rückert, JC; Neudecker, J; Falk, C; Beule, D; Sers, C; Morkel, M; Horst, D; Klauschen, F and Blüthgen, N
    The single-cell transcriptional landscape of lung carcinoid tumors.
    Int J Cancer, early online, 2022. doi  pubmed 
16. Gross, T.; Wongchenko, M.; Yan, Y. and Blüthgen, N.
    Robust network inference using response logic.
    Bioinformatics, 35: i634–i642, 2019. doi 
17. Hood, F. E. *; Klinger, B. *; Newlaczyl, A. U.; Sieber, A.; Dorel, M.; Oliver, S. P.; Coulson, J. M.; Blüthgen, N. * and Prior, I. A. *
    Isoform-specific Ras signaling is growth factor dependent.
    Molecular Biology of the Cell, 30: 1051-1128, 2019. doi  pubmed 
18. Witzel, F. and Blüthgen, N.
    When more is less: Dual phosphorylation protects signaling off-state against overexpression.
    Biophysical Journal, 115: 1383-1392, 2018. doi 
19. Dorel, M.; Klinger, B.; Sieber, A.; Prahallad, A.; Gross, T.; Bosdriesz, E.; Wessels, L. and Blüthgen, N.
    Modelling Signalling Networks from Perturbation Data.
    Bioinformatics, 34: 4079-4086, 2018. doi  pubmed 
20. Schubert, M.; Klinger, B.; Klünemann, M.; Sieber, A.; Uhlitz, F.; Sauer, S.; Garnett, M.; Blüthgen, N. and Saez-Rodriguez, J.
    Perturbation-response genes reveal signaling footprints in cancer gene expression.
    Nature Communications, 9: 20, 2018. doi  pubmed 
21. Uhlitz, F.; Sieber, A.; Wyler, E.; Fritsche-Guenther, R.; Meisig, J.; Landthaler, M.; Klinger, B. and Blüthgen, N.
    An immediate-late gene expression module decodes ERK signal duration.
    Molecular Systems Biology, 13: 928, 2017. doi 
22. Eduati, F.; Doldàn-Martelli, V.; Klinger, B.; Cokelaer, T.; Sieber, A.; Kogera, F.; Dorel, M.; Garnett, M. J.; Blüthgen, N. * and Saez-Rodriguez, J. *
    Drug resistance mechanisms in colorectal cancer dissected with cell type-specific dynamic logic models.
    Cancer Research, 77: 3364–75, 2017. doi 
23. Schulthess, P.; Löffler, A.; Vetter, S.; Kreft, L.; Schwarz, M; Braeuning, A. * and Blüthgen, N. *
    Signal Integration by the CYP1A1 Promoter – A Quantitative Study.
    Nucleic Acids Research, 43: 5318-30, 2015. doi  pubmed 
24. Schmiedel, J.M.; Klemm, S.; Zheng, Y.; Sahay, A.; Blüthgen, N. *; Marks, D.S. * and Oudenaarden, A.v. *
    
MicroRNA control of protein expression noise.
    Science, 348: 128-132, 2015. doi  pubmed 
25. Schulz, E. G; Meisig, J.; Nakamura, T.; Okamoto, I.; Sieber, A.; Picard, C.; Borensztein, M.; Saitou, M.; Blüthgen, N. and Heard, E.
    The Two Active X Chromosomes in Female ESCs Block Exit from the Pluripotent State by Modulating the ESC Signaling Network.
    Cell stem cell, 14 (2): 203-216, 2014. doi  pubmed 
26. Bentele, K.; Saffert, P.; Rauscher, R.; Ignatova, Z. and Blüthgen, N.
    Efficient translation initiation dictates codon usage at gene start.
    Molecular Systems Biology, 9: 675, 2013. doi  pubmed 
27. Klinger, B.; Sieber, A.; Fritsche-Guenther, R.; Witzel, F.; Berry, L.; Schumacher, D.; Yan, Y.; Durek, P.; Merchant, M.; Schäfer, R.; Sers, C. and Blüthgen, N.
    Network quantification of EGFR signaling unveils potential for targeted combination therapy.
    Molecular Systems Biology, 9: 673, 2013. doi  pubmed 
28. Stelniec, I; Legewie, S; Tchernitsa, O; Witzel, F; Klinger, B; Sers, C; Herzel, H; Blüthgen, N. * and Schäfer, R. *
    Reverse-engineering a hierarchical regulatory network downstream of oncogenic KRAS.
    Molecular Systems Biology, 8: 601, 2012. doi  pubmed 
29. Nora, EP; Lajoie, BR; Schulz, EG; Giorgetti, L; Okamoto, I; Servant, N; Piolot, T; Berkum, NL v.; Meisig, J; Sedat, J; Gribnau, J; Barillot, E; Blüthgen, N; Dekker, J * and Heard, E *
    Spatial partitioning of the regulatory landscape of the X-inactivation centre.
    Nature, 485: 381-385, 2012. doi  pubmed 
30. Fritsche-Guenther, R.; Witzel, F.; Sieber, A.; Herr, R.; Schmidt, N.; Braun, S.; Brummer, T.; Sers, C. and Blüthgen, N.
    Strong negative feedback from Erk to Raf confers robustness to MAPK signalling.
    Mol Syst Biol, 7: 489, 2011. doi  pubmed 
31. Parikh, J; Klinger, B; Xia, Y; Marto, JA and Blüthgen, N
    Discovering causal signaling pathways through gene expression patterns.
    Nucleic Acids Research, 38: W109-W117, 2010. doi 
32. Legewie, S.; Herzel, H.; Westerhoff, H. V and Blüthgen, N.
    Recurrent design patterns in the feedback regulation of the mammalian signalling network.
    Mol Syst Biol, 4: 190, 2008. doi  pubmed