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Unravelling the complexities of signalling networks in hepatocellular carcinoma
▸ Kim W, Khan SK, Gvozdenovic-Jeremic J, et al. Hippo signaling interactions with Wnt/ beta-catenin and Notch signaling repress liver tumorigenesis. J Clin Invest 2017;127:137–52.
Dysregulation of signalling pathways has been associated with the development and progression of a range of human cancers including hepatocellular carcinoma (HCC). A detailed understanding of how such pathways interact in vivo is essential to allow therapeutic targeting of these pathways. In this study, the authors have dissected the role of a complex signalling network involving the Hippo, Notch and Wnt/β-catenin pathways on HCC formation and growth. Inactivation of liver Hippo signalling using transgenic mice deficient for mammalian sterile 20-like kinases (MST1 and MST2) resulted in augmentation of the activity of the transcription factors YAP and TAZ and the spontaneous development of HCC in 100% of mice. Hence, the authors confirmed a tumour-suppressive role of Hippo signalling in the liver. They proceeded to use a series of in vitro and in vivo models to determine that knockout of Hippo signalling in the liver resulted in activation of the Notch signalling pathway. Blockade of the Notch pathway using a chemical inhibitor called DAPT inhibited tumour growth. Furthermore, Wnt/β-catenin signalling seems to counteract the tumourpromoting effects of Hippo knockout, at least in part via the inhibition of Notch activation. These data nicely demonstrate the fact that complex signalling networks regulate tumorigenesis in vivo and highlight the difficulties in targeting such pathways therapeutically.
That gut feeling: grown in the lab
▸ Workman MJ, Mahe MM, Trisno S, et al. Engineered human pluripotent-stem-cell-derived intestinal tissues with a functional enteric nervous system. Nat Med 2017;23:49–59.
Organoids can be a useful three-dimensional (3D) in vitro simulation for intestinal cell growth but thus far have not incorporated the enteric nervous system. Intestinal organoids can be cultured from human-induced pluripotent stem cells (PSCs). In this study, they incorporate …
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