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The Wnt enhanceosome in intestinal neoplasia
Mieszczanek J, van Tienen LM, Ibrahim AEK et al. Bcl9 and Pygo synergise downstream of Apc to effect intestinal neoplasia in FAP mouse models. Nature Communications 2019;13:10(1):724
APC, the most commonly mutated gene in colorectal cancer, controls Wnt/β-catenin signalling via the Wnt enhanceosome. This is a multiprotein complex dependent on Bcl9 transcription cofactor and its docking to chromatin-binding Pygo. A germline mutation in APC in mice (APC Min) causes multiple intestinal polyps. Conditional loss of Bcl9 or Pygo in these mice prolonged disease-free survival and the double knockout had a greater effect. Bcl9 and Pygo therefore act synergistically in regulating downstream APC genes. Surprisingly knock out of Bcl9 led to an increased number of polyps but of smaller size, suggesting that Bcl9 drives tumour growth. The double Bcl9/Pygo knockout showed a similar phenotype with RNA sequencing of polyps revealing a shift from a stem-like signature to differentiated cells. Next, the APC 1322 mouse model was used, which mimics a common APC mutation. Partial APC function is retained and there is a level of Wnt signalling that results in more rapid and severe polyposis. Here, pygo knockout led to a reduction in tumour load and extended disease-free survival. Bcl9 knockout almost abrogated the phenotype and mice showed no adenomas at 77 days. Overall, Bcl9 acts as a scaffold in the Wnt enhanceosome and partially relies on Pygo. Bcl9 is more critical than Pygo in driving intestinal neoplasia but they act synergistically. The enhanceosome likely integrates Wnt and Notch signalling, hence the switch to a differentiated phenotype. These data suggest that blocking the binding of Bcl9 to β-catenin is a potential therapeutic target in colorectal cancer.
Neutrophil–Macrophage interactions regulate tissue repair following acute liver injury
Yang W, Tao Y, Wu Y, et al. Neutrophils promote the development of reparative macrophages mediated by ROS to orchestrate liver …
Competing interests None declared.
Provenance and peer review Not commissioned; internally peer reviewed.