Healthy tissue microenvironment sustains homeostasis, evasion of which can lead to premalignant lesions. This is seen, for example, in APC-deficient intestinal stem cells (ISCs) that form adenomas, which are precursors to colorectal cancer (CRC). APC deficiency confers ISCs with an advantage, whereby they outcompete normal ISCs in the intestine. Although it is known that loss of APC leads to unchecked activation of the WNT pathway, the underlying mechanisms remain incompletely understood. Understanding how APC-deficient cells gain clonal advantage can be useful to generate strategies to prevent CRC in patients at high risk.

To analyse this stem cell competition, Flanagan et al. first performed comparative transcriptomic profiling of Apc-mutant tumours as well as Apc-mutant ISCs derived from genetically engineered mouse models (Villin-creER;Apcfl/+ and Lgr5-creER;Apcfl/fl mice). These models mimic human CRC and exhibit constitutive WNT pathway activation following loss of APC. This analysis identified upregulation of NOTUM, a secreted deacylase that inhibits WNT ligand binding to Frizzled receptors, specifically in Apc-mutant ISCs, when compared with normal ISCs.