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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Mar 31, 2019 |
| Title |
Cell type-dependent differential activation of ERK by oncogenic KRAS in human colon cancer and mouse intestinal epithelium |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
Transgene-inducible mouse intestinal organoids for KRAS, BRAF and CTNNB1 were subjected to single cell RNA-sequencing.
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| Contributor(s) |
Brandt R, Sell T, Lüthen M, Uhlitz F, Klinger B, Riemer P, Giesecke C, Schulze S, El-Shimy IA, Kunkel D, Fauler B, Mielke T, Mages N, Herrmann BG, Sers C, Blüthgen N, Morkel M |
| Citation(s) |
31266962 |
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| Submission date |
Jun 01, 2018 |
| Last update date |
Jul 16, 2019 |
| Contact name |
Florian Uhlitz |
| Organization name |
Memorial Sloan Kettering Cancer Center
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| Department |
Computational Oncology
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| Lab |
Sohrab Shah
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| Street address |
1275 York Avenue
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| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10065 |
| Country |
USA |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (8)
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| Relations |
| BioProject |
PRJNA474229 |
| SRA |
SRP149573 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE115242_norm_counts_P1-P2.tsv.gz |
1.9 Mb |
(ftp)(http) |
TSV |
| GSE115242_norm_counts_P3-P4.tsv.gz |
565.4 Kb |
(ftp)(http) |
TSV |
| GSE115242_norm_counts_P5-P8.tsv.gz |
3.0 Mb |
(ftp)(http) |
TSV |
| GSE115242_plate_anno.tsv.gz |
5.6 Kb |
(ftp)(http) |
TSV |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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