2. Academic Validation
  3. Quantifying single-cell ERK dynamics in colorectal cancer organoids reveals EGFR as an amplifier of oncogenic MAPK pathway signalling

Quantifying single-cell ERK dynamics in colorectal cancer organoids reveals EGFR as an amplifier of oncogenic MAPK pathway signalling

  • Nat Cell Biol. 2021 Apr;23(4):377-390. doi: 10.1038/s41556-021-00654-5.
Bas Ponsioen 1 2,  Jasmin B Post 1 2,  Julian R Buissant des Amorie 1 2,  Dimitrios Laskaris  # 1 2,  Ravian L van Ineveld  # 1 2,  Simone Kersten  # 1 2,  Andrea Bertotti 3 4,  Francesco Sassi 3,  François Sipieter 5 6 7,  Benjamin Cappe 5 6,  Sander Mertens 1 2,  Ingrid Verlaan-Klink 1 2,  Sylvia F Boj 8,  Rob G J Vries 8,  Holger Rehmann 1,  Peter Vandenabeele 5 6,  Franck B Riquet 5 6 9,  Livio Trusolino 3 4,  Johannes L Bos 1 2,  Hugo J G Snippert 10 11
Affiliations

Affiliations

  • 1 Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.
  • 2 Oncode Institute, Utrecht, Netherlands.
  • 3 Laboratory of Translational Cancer Medicine, Candiolo Cancer Institute - FPO IRCCs, Candiolo, Torino, Italy.
  • 4 Department of Oncology, University of Torino School of Medicine, Candiolo, Torino, Italy.
  • 5 Molecular Signaling and Cell Death Unit, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
  • 6 Molecular Signaling and Cell Death Unit, Center for Inflammation Research (IRC), a VIB-UGent department, Ghent, Belgium.
  • 7 Institut Jacques Monod, CNRS UMR 7592, Université Paris Diderot, Paris, France.
  • 8 Foundation Hubrecht Organoid Technology (HUB), Utrecht, Netherlands.
  • 9 University of Lille, Villeneuve d'Ascq, France.
  • 10 Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands. h.j.g.snippert@umcutrecht.nl.
  • 11 Oncode Institute, Utrecht, Netherlands. h.j.g.snippert@umcutrecht.nl.
  • # Contributed equally.
PMID: 33795873 DOI: 10.1038/s41556-021-00654-5
Abstract

Direct targeting of the downstream mitogen-activated protein kinase (MAPK) pathway to suppress extracellular-regulated kinase (ERK) activation in KRAS and BRaf mutant colorectal Cancer (CRC) has proven clinically unsuccessful, but promising results have been obtained with combination therapies including epidermal growth factor receptor (EGFR) inhibition. To elucidate the interplay between EGF signalling and ERK activation in tumours, we used patient-derived organoids (PDOs) from KRAS and BRaf mutant CRCs. PDOs resemble in vivo tumours, model treatment response and are compatible with live-cell microscopy. We established real-time, quantitative drug response assessment in PDOs with single-cell resolution, using our improved fluorescence resonance energy transfer (FRET)-based ERK biosensor EKAREN5. We show that oncogene-driven signalling is strikingly limited without EGFR activity and insufficient to sustain full proliferative potential. In PDOs and in vivo, upstream EGFR activity rigorously amplifies signal transduction efficiency in KRAS or BRaf mutant MAPK pathways. Our data provide a mechanistic understanding of the effectivity of EGFR inhibitors within combination therapies against KRAS and BRaf mutant CRC.

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