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Journal Article

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

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Giesecke-Thiel,  Claudia
Flow Cytometry Facility (Head: Claudia Giesecke-Thiel), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society;

/persons/resource/persons50148

Fauler,  Beatrix
Microscopy and Cryo-Electron Microscopy (Head: Thorsten Mielke), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society;

/persons/resource/persons50431

Mielke,  Thorsten
Microscopy and Cryo-Electron Microscopy (Head: Thorsten Mielke), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Mages,  Norbert
Sequencing (Head: Bernd Timmermann), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Herrmann,  Bernhard G.
Dept. of Developmental Genetics (Head: Bernhard G. Herrmann), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Brandt_2019.pdf
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Citation

Brandt, R., Sell, T., Lüthen, M., Uhlitz, F., Klinger, B., Riemer, P., et al. (2019). Cell type-dependent differential activation of ERK by oncogenic KRAS in colon cancer and intestinal epithelium. Nature Communications, 10(1): 2919. doi:10.1038/s41467-019-10954-y.


Cite as: http://hdl.handle.net/21.11116/0000-0003-5614-6
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.