Cell type-dependent differential activation of ERK by oncogenic KRAS in colon cancer and intestinal epithelium

Raphael Brandt, Thomas Sell, Mareen Lüthen, Florian Uhlitz, Bertram Klinger, Pamela Riemer, Claudia Giesecke-Thiel, Silvia Schulze, Ismail Amr El-Shimy, Desiree Kunkel, Beatrix Fauler, Thorsten Mielke, Norbert Mages, Bernhard G. Herrmann, Christine Sers, Nils Blüthgen () and Markus Morkel ()
Additional contact information
Raphael Brandt: Charité Universitätsmedizin Berlin
Thomas Sell: Charité Universitätsmedizin Berlin
Mareen Lüthen: Charité Universitätsmedizin Berlin
Florian Uhlitz: Charité Universitätsmedizin Berlin
Bertram Klinger: Charité Universitätsmedizin Berlin
Pamela Riemer: Charité Universitätsmedizin Berlin
Claudia Giesecke-Thiel: German Rheumatism Research Center, Leibniz Institute
Silvia Schulze: Charité Universitätsmedizin Berlin
Ismail Amr El-Shimy: Charité Universitätsmedizin Berlin
Desiree Kunkel: Charité - Universitätsmedizin Berlin
Beatrix Fauler: Max Planck Institute for Molecular Genetics
Thorsten Mielke: Max Planck Institute for Molecular Genetics
Norbert Mages: Max Planck Institute for Molecular Genetics
Bernhard G. Herrmann: Max Planck Institute for Molecular Genetics
Christine Sers: Charité Universitätsmedizin Berlin
Nils Blüthgen: Charité Universitätsmedizin Berlin
Markus Morkel: Charité Universitätsmedizin Berlin

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract Oncogenic mutations in KRAS or BRAF are frequent in colorectal cancer and activate the ERK kinase. Here, we find graded ERK phosphorylation correlating with cell differentiation in patient-derived colorectal cancer organoids with and without KRAS mutations. Using reporters, single cell transcriptomics and mass cytometry, we observe cell type-specific phosphorylation of ERK in response to transgenic KRASG12V in mouse intestinal organoids, while transgenic BRAFV600E activates ERK in all cells. Quantitative network modelling from perturbation data reveals that activation of ERK is shaped by cell type-specific MEK to ERK feed forward and negative feedback signalling. We identify dual-specificity phosphatases as candidate modulators of ERK in the intestine. Furthermore, we find that oncogenic KRAS, together with β-Catenin, favours expansion of crypt cells with high ERK activity. Our experiments highlight key differences between oncogenic BRAF and KRAS in colorectal cancer and find unexpected heterogeneity in a signalling pathway with fundamental relevance for cancer therapy.

Date: 2019
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DOI: 10.1038/s41467-019-10954-y

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