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Quantifying single-cell ERK dynamics in colorectal cancer organoids reveals EGFR as an amplifier of oncogenic MAPK pathway signalling.
- Source :
-
Nature cell biology [Nat Cell Biol] 2021 Apr; Vol. 23 (4), pp. 377-390. Date of Electronic Publication: 2021 Apr 01. - Publication Year :
- 2021
-
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.
- Subjects :
- Cell Line, Tumor
Colorectal Neoplasms genetics
Colorectal Neoplasms pathology
ErbB Receptors genetics
Gene Expression Regulation, Neoplastic drug effects
Humans
MAP Kinase Signaling System drug effects
Mitogen-Activated Protein Kinase Kinases genetics
Mutation
Organoids metabolism
Organoids pathology
Single-Cell Analysis
Colorectal Neoplasms drug therapy
Protein Kinase Inhibitors pharmacology
Proto-Oncogene Proteins B-raf genetics
Proto-Oncogene Proteins p21(ras) genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4679
- Volume :
- 23
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Nature cell biology
- Publication Type :
- Academic Journal
- Accession number :
- 33795873
- Full Text :
- https://doi.org/10.1038/s41556-021-00654-5