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Article Dans Une Revue Nature Cell Biology Année : 2021

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

Jasmin Post
  • Fonction : Auteur
Julian Buissant Des Amorie
  • Fonction : Auteur
Dimitrios Laskaris
  • Fonction : Auteur
Ravian van Ineveld
  • Fonction : Auteur
Simone Kersten
  • Fonction : Auteur
Andrea Bertotti
  • Fonction : Auteur
Francesco Sassi
  • Fonction : Auteur
Benjamin Cappe
Sander Mertens
  • Fonction : Auteur
Ingrid Verlaan-Klink
  • Fonction : Auteur
Sylvia Boj
  • Fonction : Auteur
Rob Vries
  • Fonction : Auteur
Holger Rehmann
  • Fonction : Auteur
Peter Vandenabeele
Franck Riquet
  • Fonction : Auteur
Livio Trusolino
  • Fonction : Auteur
Johannes Bos
  • Fonction : Auteur
Hugo Snippert
  • Fonction : Auteur

Résumé

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.

Dates et versions

hal-03255726 , version 1 (09-06-2021)

Identifiants

Citer

Bas Ponsioen, Jasmin Post, Julian Buissant Des Amorie, Dimitrios Laskaris, Ravian van Ineveld, et al.. Quantifying single-cell ERK dynamics in colorectal cancer organoids reveals EGFR as an amplifier of oncogenic MAPK pathway signalling. Nature Cell Biology, 2021, 23 (4), pp.377-390. ⟨10.1038/s41556-021-00654-5⟩. ⟨hal-03255726⟩
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