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

Autor: Ponsioen B; Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.; Oncode Institute, Utrecht, Netherlands., Post JB; Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.; Oncode Institute, Utrecht, Netherlands., Buissant des Amorie JR; Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.; Oncode Institute, Utrecht, Netherlands., Laskaris D; Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.; Oncode Institute, Utrecht, Netherlands., van Ineveld RL; Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.; Oncode Institute, Utrecht, Netherlands., Kersten S; Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.; Oncode Institute, Utrecht, Netherlands., Bertotti A; Laboratory of Translational Cancer Medicine, Candiolo Cancer Institute - FPO IRCCs, Candiolo, Torino, Italy.; Department of Oncology, University of Torino School of Medicine, Candiolo, Torino, Italy., Sassi F; Laboratory of Translational Cancer Medicine, Candiolo Cancer Institute - FPO IRCCs, Candiolo, Torino, Italy., Sipieter F; Molecular Signaling and Cell Death Unit, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.; Molecular Signaling and Cell Death Unit, Center for Inflammation Research (IRC), a VIB-UGent department, Ghent, Belgium.; Institut Jacques Monod, CNRS UMR 7592, Université Paris Diderot, Paris, France., Cappe B; Molecular Signaling and Cell Death Unit, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.; Molecular Signaling and Cell Death Unit, Center for Inflammation Research (IRC), a VIB-UGent department, Ghent, Belgium., Mertens S; Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.; Oncode Institute, Utrecht, Netherlands., Verlaan-Klink I; Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.; Oncode Institute, Utrecht, Netherlands., Boj SF; Foundation Hubrecht Organoid Technology (HUB), Utrecht, Netherlands., Vries RGJ; Foundation Hubrecht Organoid Technology (HUB), Utrecht, Netherlands., Rehmann H; Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands., Vandenabeele P; Molecular Signaling and Cell Death Unit, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.; Molecular Signaling and Cell Death Unit, Center for Inflammation Research (IRC), a VIB-UGent department, Ghent, Belgium., Riquet FB; Molecular Signaling and Cell Death Unit, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.; Molecular Signaling and Cell Death Unit, Center for Inflammation Research (IRC), a VIB-UGent department, Ghent, Belgium.; University of Lille, Villeneuve d'Ascq, France., Trusolino L; Laboratory of Translational Cancer Medicine, Candiolo Cancer Institute - FPO IRCCs, Candiolo, Torino, Italy.; Department of Oncology, University of Torino School of Medicine, Candiolo, Torino, Italy., Bos JL; Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.; Oncode Institute, Utrecht, Netherlands., Snippert HJG; Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands. h.j.g.snippert@umcutrecht.nl.; Oncode Institute, Utrecht, Netherlands. h.j.g.snippert@umcutrecht.nl.
Jazyk: angličtina
Zdroj: Nature cell biology [Nat Cell Biol] 2021 Apr; Vol. 23 (4), pp. 377-390. Date of Electronic Publication: 2021 Apr 01.
DOI: 10.1038/s41556-021-00654-5
Abstrakt: 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.
Databáze: MEDLINE
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