NSUN2 drives intestinal stem cell expansion and colorectal tumour initiation via MAPK/ERK signalling

Colorectal cancer is initiated by loss of the APC gene, which drives expansion of LGR5+ intestinal stem cell (ISC) populations. Whilst LGR5+ ISC expansion is a critical step for tumour initiation and progression, its regulation is poorly understood. Emerging evidence suggests post-transcriptional RNA modifications play a key role in cancer biology, but their role in CRC initiation has not been explored. Here, we identify the m ⁵ C methyltransferase NSUN2 as a key regulator of ISC expansion and intestinal tumourigenesis. NSUN2 is upregulated in multiple CRC mouse models and human tumours and its depletion impairs ISC expansion and hyperproliferation, leading to reduced tumour initiation. Transcriptome-wide bisulphite sequencing revealed that NSUN2-mediates m ⁵ C methylation on mRNAs encoding key ISC regulators and components of the MAPK/ERK pathway. Mechanistically, loss of NSUN2 reduces ERK phosphorylation in Apc- deficient models and oncogenic Kras ^G12D expression is sufficient to restore ERK signalling and rescue ISC expansion. Together, this establishes NSUN2 as a key regulator of ISC-driven CRC initiation and describes a novel molecular mechanism linking m ⁵ C methylation to MAPK driven stem cell transformation.