{Reference Type}: Journal Article
{Title}: Mitogen-activated protein kinase activity drives cell trajectories in colorectal cancer.
{Author}: 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 TT;Klotz-Noack K;Schwarz RF;Sawitzki B;Kamphues C;Beule D;Landthaler M;Sers C;Horst D;Blüthgen N;Morkel M;
{Journal}: EMBO Mol Med
{Volume}: 13
{Issue}: 10
{Year}: 10 2021 7
{Factor}: 14.26
{DOI}: 10.15252/emmm.202114123
{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.