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

Author

Listed:
  • Raphael Brandt

    (Charité Universitätsmedizin Berlin)

  • Thomas Sell

    (Charité Universitätsmedizin Berlin
    Humboldt University Berlin)

  • Mareen Lüthen

    (Charité Universitätsmedizin Berlin
    German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ))

  • Florian Uhlitz

    (Charité Universitätsmedizin Berlin
    Humboldt University Berlin
    German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ))

  • Bertram Klinger

    (Charité Universitätsmedizin Berlin
    Humboldt University Berlin)

  • Pamela Riemer

    (Charité Universitätsmedizin Berlin)

  • Claudia Giesecke-Thiel

    (German Rheumatism Research Center, Leibniz Institute
    Max Planck Institute for Molecular Genetics)

  • Silvia Schulze

    (Charité Universitätsmedizin Berlin)

  • Ismail Amr El-Shimy

    (Charité Universitätsmedizin Berlin
    Humboldt University 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
    Charité Universitätsmedizin Berlin)

  • Christine Sers

    (Charité Universitätsmedizin Berlin
    German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
    Berlin Institute of Health (BIH))

  • Nils Blüthgen

    (Charité Universitätsmedizin Berlin
    Humboldt University Berlin
    German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
    Berlin Institute of Health (BIH))

  • Markus Morkel

    (Charité Universitätsmedizin Berlin
    German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
    Berlin Institute of Health (BIH))

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.

Suggested Citation

  • 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 & Thor, 2019. "Cell type-dependent differential activation of ERK by oncogenic KRAS in colon cancer and intestinal epithelium," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10954-y
    DOI: 10.1038/s41467-019-10954-y
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    Cited by:

    1. Carmen Aguilar & Mindaugas Pauzuolis & Malvika Pompaiah & Ehsan Vafadarnejad & Panagiota Arampatzi & Mara Fischer & Dominik Narres & Mastura Neyazi & Özge Kayisoglu & Thomas Sell & Nils Blüthgen & Mar, 2022. "Helicobacter pylori shows tropism to gastric differentiated pit cells dependent on urea chemotaxis," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Mathurin Dorel & Bertram Klinger & Tommaso Mari & Joern Toedling & Eric Blanc & Clemens Messerschmidt & Michal Nadler-Holly & Matthias Ziehm & Anja Sieber & Falk Hertwig & Dieter Beule & Angelika Egge, 2021. "Neuroblastoma signalling models unveil combination therapies targeting feedback-mediated resistance," PLOS Computational Biology, Public Library of Science, vol. 17(11), pages 1-26, November.
    3. Huiyuan Zhu & Man Li & Dexi Bi & Huiqiong Yang & Yaohui Gao & Feifei Song & Jiayi Zheng & Ruting Xie & Youhua Zhang & Hu Liu & Xuebing Yan & Cheng Kong & Yefei Zhu & Qian Xu & Qing Wei & Huanlong Qin, 2024. "Fusobacterium nucleatum promotes tumor progression in KRAS p.G12D-mutant colorectal cancer by binding to DHX15," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    4. Arafath K. Najumudeen & Sigrid K. Fey & Laura M. Millett & Catriona A. Ford & Kathryn Gilroy & Nuray Gunduz & Rachel A. Ridgway & Eve Anderson & Douglas Strathdee & William Clark & Colin Nixon & Jenni, 2024. "KRAS allelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancer in vivo," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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