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DFG-Project "Systematic analyses of CTNNB1-, BRAF-, KRAS- and PIK3CA-induced oncogenic activities in the intestinal epithelium".

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Project description

Colon cancer cells contain sets of recurring mutations that alter the activities of key signalling pathways, among these the Wnt/beta-Catenin, Mitogen-activated protein kinase (MAPK), and the Phosphatidylinositol-3-kinase (PI3K) pathways that regulate stem cell traits, proliferation, differentiation and apoptosis in the normal intestinal epithelium. The contribution of specific oncoproteins to the cancer phenotype is difficult to dissect, since many mutated proteins contribute simultaneously to aberrant signalling. We have therefore in the last years established a series of transgenic mouse and organoid models that allow induction of oncogenic forms of CTNNB1, KRAS, BRAF or PIK3CA alone or in combinations, using tetracycline-controlled transgene expression. We use these models to analyse oncogenic signalling, as well as changes in cell composition and transcriptomes in a systematic manner. To dissect oncogenic signalling networks, we interfere with signal transduction using small molecular inhibitors.

Figure legend

Using CTNNB1(stab)- and PIK3CA(H1047R)-inducible organoids to dissect cancer phenotypes. A) Network quantification by capillary (phospho)-protein analysis and phenotyping after oncogene induction and inhibitor treatment B) Diagram of signaling network under investigation. Oncogenes are given in yellow and red; inhibitors are given in blue. C) LASSO analysis identifies p4EBP1 and pAKT as network components most closely associated with cell survival and motility, respectively. (Figure modified from Riemer et al., J. Cell Biol. 2017).

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