Quantifying single-cell ERK dynamics in colorectal cancer organoids reveals EGFR as an amplifier of oncogenic MAPK pathway signalling
| Autor: | Livio Trusolino, Francesco Sassi, Sander Mertens, Benjamin Cappe, Ingrid Verlaan-Klink, Ravian L. van Ineveld, Bas Ponsioen, Sylvia F. Boj, Simone Kersten, Julian R. Buissant des Amorie, Dimitrios Laskaris, Rob G. J. Vries, Franck B. Riquet, Andrea Bertotti, Jasmin B. Post, François Sipieter, Johannes L. Bos, Peter Vandenabeele, Hugo J. Snippert, Holger Rehmann |
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| Přispěvatelé: | University Medical Center [Utrecht], Department of Biomedical Molecular Biology [Ghent], Universiteit Gent = Ghent University [Belgium] (UGENT), Institut Jacques Monod (IJM (UMR_7592)), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP) |
| Rok vydání: | 2020 |
| Předmět: |
MAPK/ERK pathway
endocrine system diseases cell-to-cell heterogeneity pan-HER inhibition [SDV]Life Sciences [q-bio] Mitogen-activated protein kinase kinase medicine.disease_cause 0302 clinical medicine Epidermal growth factor receptor oncogenic signaling EGFR inhibitors 0303 health sciences Tumor biology Kinase Chemistry 3. Good health Cell biology ErbB Receptors Gene Expression Regulation Neoplastic Organoids 030220 oncology & carcinogenesis KRAS Signal transduction Single-Cell Analysis Colorectal Neoplasms patient-derived organoids Proto-Oncogene Proteins B-raf MAP Kinase Signaling System EGFR FRET biosensors Article Cell Line Proto-Oncogene Proteins p21(ras) 03 medical and health sciences Cell Line Tumor medicine Humans Protein kinase A neoplasms Protein Kinase Inhibitors 030304 developmental biology Mitogen-Activated Protein Kinase Kinases Neoplastic Cell Biology ERK oscillations Colorectal cancer digestive system diseases Gene Expression Regulation Mutation biology.protein |
| Zdroj: | Nature cell biology Nature Cell Biology Nature Cell Biology, Nature Publishing Group, 2021, 23 (4), pp.377-390. ⟨10.1038/s41556-021-00654-5⟩ |
| ISSN: | 1476-4679 1465-7392 |
| Popis: | 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. Ponsioen et al. use a FRET‐based ERK biosensor EKAREN5 in patient‐derived organoids to show that EGFR activity amplifies signal transduction efficiency in KRAS or BRAF mutant MAPK pathways. |
| Databáze: | OpenAIRE |
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