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Mitogen-activated protein kinase activity drives cell trajectories in colorectal cancer

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Item Type:Article
Title:Mitogen-activated protein kinase activity drives cell trajectories in colorectal cancer
Creators Name:Uhlitz, F. and Bischoff, P. and Peidli, S. and Sieber, A. and Trinks, A. and Lüthen, M. and Obermayer, B. and Blanc, E. and Ruchiy, Y. and Sell, T. and Mamlouk, S. and Arsie, R. and Wei, T.T. and Klotz-Noack, K. and Schwarz, R.F. and Sawitzki, B. and Kamphues, C. and Beule, D. and Landthaler, M. and Sers, C. and Horst, D. and 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, Animals, Mice
Source:EMBO Molecular Medicine
ISSN:1757-4676
Publisher:Wiley
Page Range:e14123
Date:19 August 2021
Official Publication:https://doi.org/10.15252/emmm.202114123
PubMed:View item in PubMed

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