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| Item Type: | Article |
|---|---|
| Title: | Mitogen-activated protein kinase activity drives cell trajectories in colorectal cancer |
| Creators Name: | Uhlitz, F., Bischoff, P., Peidli, S., Sieber, A., Trinks, A., Lüthen, M., Obermayer, B., Blanc, E., Ruchiy, Y., Sell, T., Mamlouk, S., Arsie, R., Wei, T.T., Klotz-Noack, K., Schwarz, R.F., Sawitzki, B., Kamphues, C., Beule, D., Landthaler, M., Sers, C., Horst, D., Blüthgen, N. and Morkel, M. |
| Abstract: | In colorectal cancer, oncogenic mutations transform a hierarchically organized and homeostatic epithelium into invasive cancer tissue lacking visible organization. We sought to define transcriptional states of colorectal cancer cells and signals controlling their development by performing single-cell transcriptome analysis of tumors and matched non-cancerous tissues of twelve colorectal cancer patients. We defined patient-overarching colorectal cancer cell clusters characterized by differential activities of oncogenic signaling pathways such as mitogen-activated protein kinase and oncogenic traits such as replication stress. RNA metabolic labeling and assessment of RNA velocity in patient-derived organoids revealed developmental trajectories of colorectal cancer cells organized along a mitogen-activated protein kinase activity gradient. This was in contrast to normal colon organoid cells developing along graded Wnt activity. Experimental targeting of EGFR-BRAF-MEK in cancer organoids affected signaling and gene expression contingent on predictive KRAS/BRAF mutations and induced cell plasticity overriding default developmental trajectories. Our results highlight directional cancer cell development as a driver of non-genetic cancer cell heterogeneity and re-routing of trajectories as a response to targeted therapy. |
| Keywords: | Cancer Profiling, ERK, RNA Velocity, Single-Cell RNA Sequencing, SLAM-Seq |
| Source: | EMBO Molecular Medicine |
| ISSN: | 1757-4676 |
| Publisher: | EMBO Press / Wiley |
| Volume: | 13 |
| Number: | 10 |
| Page Range: | e14123 |
| Date: | 7 October 2021 |
| Official Publication: | https://doi.org/10.15252/emmm.202114123 |
| PubMed: | View item in PubMed |
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