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| Item Type: | Article |
|---|---|
| Title: | Mitogen-activated protein kinase activity drives cell trajectories in colorectal cancer |
| Creators: |
Uhlitz, F.  ORCID: https://orcid.org/0000-0001-9176-4660, Bischoff, P. ORCID: https://orcid.org/0000-0002-4442-7116, Peidli, S. ORCID: https://orcid.org/0000-0002-4257-8690, Sieber, A., Trinks, A. ORCID: https://orcid.org/0000-0001-9983-1506, Lüthen, M. ORCID: https://orcid.org/0000-0001-5557-6419, Obermayer, B. ORCID: https://orcid.org/0000-0002-9116-630X, Blanc, E. ORCID: https://orcid.org/0000-0002-4369-0254, Ruchiy, Y., Sell, T. ORCID: https://orcid.org/0000-0002-5138-3967, Mamlouk, S. ORCID: https://orcid.org/0000-0001-7285-1320, Arsie, R. ORCID: https://orcid.org/0000-0002-7869-7624, Wei, T.T. ORCID: https://orcid.org/0000-0001-5719-721X, Klotz-Noack, K., Schwarz, R.F. ORCID: https://orcid.org/0000-0001-9155-4268, Sawitzki, B., Kamphues, C., Beule, D. ORCID: https://orcid.org/0000-0002-3284-0632, Landthaler, M. ORCID: https://orcid.org/0000-0002-1075-8734, Sers, C., Horst, D. ORCID: https://orcid.org/0000-0003-4755-5743, Blüthgen, N. ORCID: https://orcid.org/0000-0002-0171-7447 and Morkel, M. ORCID: https://orcid.org/0000-0002-2553-9999
|
| 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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