Colorectal cancer (CRC) is one of the most pressing health challenges worldwide and in Singapore. It is the most common cancer in men and the second most common in women locally, with late diagnosis and relapse after treatment being the major causes of lethality. A key difficulty in tackling CRC is that the colon is not uniform. It is compartmentalised into different regions that give rise to distinct cancer profiles. This makes CRC a highly heterogeneous disease and complicates efforts to develop broadly effective treatments.

Until now, most CRC mouse models either lacked colon tissue-specificity or did not allow researchers to study how resident stem cells serve as the origins of cancer. This has limited our ability to model disease initiation and progression into advanced stages.

A research team led by Prof Nick Barker, Senior Investigator at A*STAR IMCB and Adjunct Professor at the NUS Yong Loo Lin School of Medicine, together with Dr Maxime Gasnier, Senior Scientist at IMCB, has made a breakthrough in this area. In a study published in Nature Cell Biology, the team identified two region-specific colon stem cell markers, NOX1 and NPY1R, that are enriched in stem cells located in different compartments of the colon.

Using these discoveries, the researchers developed new stem cell Cre drivers that, for the first time, enable selective targeting of cancer-causing mutations to distinct regions of the colon. This provides an essential platform for modelling the different types of advanced CRC that develop in humans. Importantly, the new models accurately capture both cancer initiation and progression to invasive stages, offering unprecedented opportunities to decipher the underlying mechanisms of disease, discover novel biomarkers, and evaluate therapeutic strategies.

“This work identifies stem cell populations in different parts of the colon as major sources of cancer and offers new opportunities to develop accurate models of advanced colon cancer for identifying new disease biomarkers, therapeutic targets and for pre-clinical evaluation of new cancer therapeutics,” said Prof Barker.

The findings set the stage for deeper understanding of how regional stem cell populations drive cancer and provide the research community with powerful new models to accelerate pre-clinical testing of colorectal cancer therapies.

Gasnier M, Chen TCY, Yada S, Sagiraju S, Yoshikawa Y, Perna S, Lim HYG, Lee B, Barker N. NOX1 and NPY1R mark regional colon stem cell populations that serve as cancer origins in vivo. Nat Cell Biol. 2025. doi: 10.1038/s41556-025-01763-1