Stabilisation of β-Catenin-WNT signalling by USP10 in APC-truncated colorectal cancer drives cancer stemness and enables super-competitor signalling

The contribution of deubiquitylating enzymes to β-Catenin stabilisation in intestinal stem cells and colorectal cancer (CRC) is poorly understood. Here, we report the deubiquitylase USP10 as APC-truncation- specific regulator enhancer of β-Catenin stability, potentiating WNT signalling pathway in CRC and cancer stem cells. Mechanistically, interaction studies in various CRC cell lines and in vitro binding studies, together with computational modelling, revealed that USP10 binding to β-Catenin is mediated via its USP10 unstructured N-terminus and requires truncated in the absence of full-length APC. Notably, loss of USP10 in CRISPR engineered intestinal organoids reduces tumorigenic properties of CRC cells and organoids, and blocks the super competitor-properties of APC-mutated intestinal cells, elicits induces the expression of differentiation genes, and opposes the APC-truncated phenotype in an intestinal hyperplasia model of D.melanogaster. Taken together, our findings reveal USP10s role in intestinal tumourigenesis by stabilising β-Catenin, leading to aberrant WNT signalling, enhancing cancer cell stemness and implicate the DUB USP10 as a cancer specific therapeutic vulnerability in Apc truncated CRC.