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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 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.


DOI

doi:10.15252/emmm.202114123