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Cell type-dependent differential activation of ERK by oncogenic KRAS in human colon cancer and mouse intestinal epithelium

UID: 11049

Author(s): Brandt, Raphael, Sell, Thomas, Lüthen, Mareen, Uhlitz, Florian*, Klinger, Bertram, Riemer, Pamela, Giesecke-Thiel, Claudia, Schulze, Silvia, El-Shimy, Ismail Amr, Kunkel, Desiree, Fauler, Beatrix, Mielke, Thorsten, Mages, Norbert, Herrmann, Bernhard G, Sers, Christine, Blüthgen, Nils, Morkel, Marcus * MSK affiliated

Description
Summary from GEO:

"Mutations activating the KRAS GTPase or the BRAF kinase are frequent in colorectal cancer and are thought to constitutively activate the terminal mitogen-activated protein kinase, ERK. Using mass cytometry, we found graded phosphorylation of ERK anti-correlated with cell differentiation in patient-derived colorectal cancer organoids, and unexpectedly this gradient was observed independently of KRAS mutational status. We therefore investigated differentiation-dependent signal transduction elicited by oncogenic KRAS or BRAF in transgenic mouse organoid models. Reporter, single cell transcriptome and mass cytometry analyses showed that transgenic expression of KRASG12V activated ERK in a cell type-specific pattern. Furthermore, expression of oncogenic KRAS induced the formation of RAS-ERK-responsive cells. In contrast, transgenic expression of BRAFV600E triggered high ERK activity and downstream gene expression in all intestinal cell types, followed by epithelial disorganisation. We analysed signal transduction to ERK using single cell-resolved network perturbation data in transgenic organoids. Network reconstruction followed by quantitative modelling revealed that activation of ERK is shaped by cell type-specific MEK to ERK feed forward and negative feedback signalling. We identify dual-specificity phosphatases as candidate modulators of MEK to ERK signal transduction. Our experiments highlight key differences between ERK activity elicited by the BRAF or KRAS oncogenes in colorectal cancer and find unexpected functional heterogeneity in a signalling pathway with fundamental relevance for cancer therapy."

Overall design from GEO:

"Transgene-inducible mouse intestinal organoids for KRAS, BRAF and CTNNB1 were subjected to single cell RNA-sequencing."
Subject of Study
Mus musculus
Subject(s)
Cell Differentiation
Colonic Neoplasms
Genes, ras
Mitogen-Activated Protein Kinases
Phosphorylation
Proto-Oncogene Proteins B-raf
RNA-Seq
Single-Cell Analysis
Access via GEO


Accession #: GSE115242

Access via BioProject


Accession #: PRJNA474229

Access via SRA


Accession #: SRP149573

Access Restrictions
Free to All
Access Instructions
The NCBI Gene Expression Omnibus. BioProject, and SRA databases provide open access to these files.
Associated Publications
Brandt R, Sell T, Lüthen M, Uhlitz F, Klinger B, Riemer P, Giesecke-Thiel C, Schulze S, El-Shimy IA, Kunkel D, Fauler B, Mielke T, Mages N, Herrmann BG, Sers C, Blüthgen N, Morkel M. Cell type-dependent differential activation of ERK by oncogenic KRAS in colon cancer and intestinal epithelium. Nat Commun. 2019 Jul 2;10(1):2919. PMID: 31266962; PMCID: PMC6606648.
Equipment Used
Illumina NextSeq 500
Dataset Format(s)
TSV
Dataset Size
1.9 MB (TSV), 565.4 Kb (TSV), 3 MB (TSV), 5.6 KB (TSV)
Data Catalog Record Updated
2023-11-17