Intestinal tumorigenesis often involves Wnt pathway activation and subsequent transformation and expansion of the intestinal crypt stem cell compartment. Greten and colleagues now reveal that this process may also involve dedifferentiation of non-stem intestinal epithelial cells into tumour-initiating cells (Cell 152, 25–38; 2013 ).

The authors observed that a genetic mouse model harbouring constitutively active β-catenin in intestinal epithelial cells (IECs) exhibited expansion of intestinal crypt stem cells, reduction of differentiated enterocytes and NF-κB pathway activation in IECs. Concomitant genetic inhibition of NF-κB signalling increased mouse survival by reducing crypt stem cell expansion, downregulating Wnt-pathway-dependent target genes associated with intestinal stem cells and promoting expression of genes associated with a more differentiated phenotype. These effects were attributable to the direct interaction of NF-κB with β-catenin to regulate gene transcription. Combined genetic activation of the Wnt and NF-κB pathways increased proliferative crypt stem cell numbers, and also led to the formation of crypt-like foci outside the villus epithelium, suggesting that these originated from non-stem villus cells that acquired stem cell properties. Using ex vivo organoid culture and in vivo mouse genetic-lineage tracing experiments, the authors demonstrated that non-stem IECs could indeed dedifferentiate and obtain tumour-initiating properties following hyperactivation of β-catenin. These findings demonstrate that conversion between non-stem and stem-like cell types can promote tumour initiation and highlight the importance of cell-type plasticity in cancer development.