PT - JOURNAL ARTICLE AU - Raphael Brandt AU - Thomas Sell AU - Mareen Lüthen AU - Florian Uhlitz AU - Bertram Klinger AU - Pamela Riemer AU - Claudia Giesecke-Thiel AU - Silvia Schulze AU - Ismail Amr El-Shimy AU - Desiree Kunkel AU - Beatrix Fauler AU - Thorsten Mielke AU - Norbert Mages AU - Bernhard G Herrmann AU - Christine Sers AU - Nils Blüthgen AU - Markus Morkel TI - Cell type-dependent differential activation of ERK by oncogenic KRAS in colon cancer and intestinal epithelium AID - 10.1101/340844 DP - 2019 Jan 01 TA - bioRxiv PG - 340844 4099 - http://biorxiv.org/content/early/2019/02/14/340844.short 4100 - http://biorxiv.org/content/early/2019/02/14/340844.full AB - Mutations activating the KRAS GTPase or the BRAF kinase are frequent in colorectal cancer and are thought to constitutively activate the terminal mitogen-activated protein kinase, ERK. Using mass cytometry, we found graded phosphorylation of ERK anti-correlated with cell differentiation in patient-derived colorectal cancer organoids, independent of KRAS mutational status. Reporter, single cell transcriptome and mass cytometry analyses showed that transgenic KRASG12V activated ERK in a cell type-specific pattern in mouse intestinal organoids. In contrast, transgenic BRAFV600E triggered high ERK activity and downstream gene expression in all intestinal cell types, followed by epithelial disorganisation. Quantitative network modelling from perturbation data revealed that activation of ERK is shaped by cell type-specific MEK to ERK feed forward and negative feedback signalling. We identified dual-specificity phosphatases as candidate modulators of ERK activity between intestinal cell types. Furthermore, we found that oncogenic KRAS, together with β-Catenin, favoured expansion of crypt cells with high ERK activity. Our experiments highlight key differences between ERK activity elicited by the BRAF or KRAS oncogenes in colorectal cancer and find unexpected heterogeneity in a signalling pathway with fundamental relevance for cancer therapy.