Colorectal cancer progression is intrinsically linked to stepwise deregulation of the intestinal differentiation trajectory. In this process, sequential mutations of APC, KRAS, TP53, and SMAD4 enable oncogenic signaling and establish the hallmarks of cancer. Here, we use mass cytometry of isogenic human colon organoids and patient-derived cancer organoids to capture oncogenic signaling, cell phenotypes, and differentiation states in a high-dimensional single-cell map. We define a differentiation axis in all tumor progression states from normal to cancer. Our data show that colorectal cancer driver mutations shape the distribution of cells along the differentiation axis. In this regard, subsequent mutations can have stem cell promoting or restricting effects. Individual nodes of the cancer cell signaling network remain coupled to the differentiation state, regardless of the presence of driver mutations. We use single-cell RNA sequencing to link the (phospho-)protein signaling network to transcriptomic states with biological and clinical relevance. Our work highlights how oncogenes gradually shape signaling and transcriptomes during tumor progression.
Oncogenic signaling is coupled to colorectal cancer cell differentiation state
Disclosures: H. Clevers reported a patent to PCT/NL2010/000017 WO2010/090513 issued “Foundation HUB”; and “Since March 2022, I am a full-time member of the executive board of F. Hoffmann-La Roche Ltd. as head of Pharma, Research and Early Development (pRED) in Basel, Switzerland.” No other disclosures were reported.
H. Clevers’s current affiliation is Pharma, Research and Early Development of F. Hoffmann-La Roche Ltd., Basel, Switzerland.
- Award Id(s): RTG2424,2783/5
- Award Id(s): 02NUK047E,161 L0220A,16LW0239K
Thomas Sell, Christian Klotz, Matthias M. Fischer, Rosario Astaburuaga-García, Susanne Krug, Jarno Drost, Hans Clevers, Christine Sers, Markus Morkel, Nils Blüthgen; Oncogenic signaling is coupled to colorectal cancer cell differentiation state. J Cell Biol 5 June 2023; 222 (6): e202204001. doi: https://doi.org/10.1083/jcb.202204001
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