Mitogen-activated protein kinase activity drives cell trajectories in colorectal cancer
Authors
- F. Uhlitz
- P. Bischoff
- S. Peidli
- A. Sieber
- A. Trinks
- M. Lüthen
- B. Obermayer
- E. Blanc
- Y. Ruchiy
- T. Sell
- S. Mamlouk
- R. Arsie
- T.T. Wei
- K. Klotz-Noack
- R.F. Schwarz
- B. Sawitzki
- C. Kamphues
- D. Beule
- M. Landthaler
- C. Sers
- D. Horst
- N. Blüthgen
- M. Morkel
Journal
- EMBO Molecular Medicine
Citation
- EMBO Mol Med 13 (10): e14123
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.