Nox1 and Npy1r mark regional colon stem cell populations that serve as cancer origins in vivo [RNA-seq2]

Current colorectal cancer (CRC) mouse models lack either colon specificity, limiting progression towards more advanced disease, or preclude evaluation of resident stem cells as cancer origins. Here, we report identification of Nox1 and Npy1r as cell-surface markers enriched in Lgr5+ stem cells predominantly within the caecum and exclusively within the mid-distal colorectum respectively. Selective dysregulation of Wnt signalling in Nox1+ or Npy1r+ stem cells using new CreERT2 mouse lines drives colon cancer initiation, predominantly within the caecum and the rectum respectively, establishing these stem cell populations as important sources of colon cancer. Selective conditional activation of Wnt signalling and oncogenic K-RAS in combination with loss of Trp53 in these stem cell compartments resulted in development of advanced, invasive cancers. This study establishes the new CreERT2 drivers as valuable tools for studying stem cell contributions to colon cancer.