TY - JOUR T1 - Oncogenic signalling is coupled to colorectal cancer cell differentiation state JF - bioRxiv DO - 10.1101/2022.04.07.487491 SP - 2022.04.07.487491 AU - Thomas Sell AU - Christian Klotz AU - Matthias M. Fischer AU - Rosario Astaburuaga-García AU - Susanne Krug AU - Jarno Drost AU - Hans Clevers AU - Markus Morkel AU - Nils Blüthgen Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/04/08/2022.04.07.487491.abstract N2 - Colorectal cancer progression is intrinsically linked to stepwise deregulation of the intestinal differentiation trajectory. In this process, sequential mutations of APC/Wnt, KRAS, TP53 and SMAD4 stepwisely enable an oncogenic signalling network. Here, we developed a novel mass cytometry antibody panel to analyse colorectal cancer cell differentiation and signalling in human isogenic colorectal cancer organoids and in patient-derived cultures. We define a differentiation axis following EphrinB2 abundance in all tumour progression states from normal to cancer. We show that during colorectal cancer progression, oncogenes decrease dependence on external factors and shape distribution of cells along the differentiation axis. In this regard, subsequent mutations can have stem cell-promoting or restricting effects. Individual nodes of the signalling network remain coupled to the differentiation state, regardless of the presence of oncogenic signals. Our work underscores the key role of cell plasticity as a hallmark of cancer that is gradually unlocked during colorectal cancer progression.Competing Interest StatementThe authors have declared no competing interest. ER -