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MEK inhibitors activate Wnt signalling and induce stem cell plasticity in colorectal cancer

Author

Listed:
  • Tianzuo Zhan

    (German Cancer Research Center (DKFZ) and Heidelberg University
    Heidelberg University)

  • Giulia Ambrosi

    (German Cancer Research Center (DKFZ) and Heidelberg University)

  • Anna Maxi Wandmacher

    (German Cancer Research Center (DKFZ) and Heidelberg University)

  • Benedikt Rauscher

    (German Cancer Research Center (DKFZ) and Heidelberg University)

  • Johannes Betge

    (German Cancer Research Center (DKFZ) and Heidelberg University
    Heidelberg University)

  • Niklas Rindtorff

    (German Cancer Research Center (DKFZ) and Heidelberg University)

  • Ragna S. Häussler

    (NMI Natural and Medical Sciences Institute at the University of Tübingen)

  • Isabel Hinsenkamp

    (Heidelberg University)

  • Leonhard Bamberg

    (Heidelberg University)

  • Bernd Hessling

    (German Cancer Research Center (DKFZ))

  • Karin Müller-Decker

    (German Cancer Research Center (DKFZ))

  • Gerrit Erdmann

    (NMI TT Pharmaservices)

  • Elke Burgermeister

    (Heidelberg University)

  • Matthias P. Ebert

    (Heidelberg University)

  • Michael Boutros

    (German Cancer Research Center (DKFZ) and Heidelberg University)

Abstract

In colorectal cancer (CRC), aberrant Wnt signalling is essential for tumorigenesis and maintenance of cancer stem cells. However, how other oncogenic pathways converge on Wnt signalling to modulate stem cell homeostasis in CRC currently remains poorly understood. Using large-scale compound screens in CRC, we identify MEK1/2 inhibitors as potent activators of Wnt/β-catenin signalling. Targeting MEK increases Wnt activity in different CRC cell lines and murine intestine in vivo. Truncating mutations of APC generated by CRISPR/Cas9 strongly synergize with MEK inhibitors in enhancing Wnt responses in isogenic CRC models. Mechanistically, we demonstrate that MEK inhibition induces a rapid downregulation of AXIN1. Using patient-derived CRC organoids, we show that MEK inhibition leads to increased Wnt activity, elevated LGR5 levels and enrichment of gene signatures associated with stemness and cancer relapse. Our study demonstrates that clinically used MEK inhibitors inadvertently induce stem cell plasticity, revealing an unknown side effect of RAS pathway inhibition.

Suggested Citation

  • Tianzuo Zhan & Giulia Ambrosi & Anna Maxi Wandmacher & Benedikt Rauscher & Johannes Betge & Niklas Rindtorff & Ragna S. Häussler & Isabel Hinsenkamp & Leonhard Bamberg & Bernd Hessling & Karin Müller-, 2019. "MEK inhibitors activate Wnt signalling and induce stem cell plasticity in colorectal cancer," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09898-0
    DOI: 10.1038/s41467-019-09898-0
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    Cited by:

    1. Johannes Betge & Niklas Rindtorff & Jan Sauer & Benedikt Rauscher & Clara Dingert & Haristi Gaitantzi & Frank Herweck & Kauthar Srour-Mhanna & Thilo Miersch & Erica Valentini & Kim E. Boonekamp & Vero, 2022. "The drug-induced phenotypic landscape of colorectal cancer organoids," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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