Zeb2 drives invasive and microbiota-dependent colon carcinoma

Abstract

Colorectal cancer (CRC) is highly prevalent in Western society, and increasing evidence indicates strong contributions of environmental factors and the intestinal microbiota to CRC initiation, progression and even metastasis. We have identified a synergistic inflammatory tumor-promoting mechanism through which the resident intestinal microbiota boosts invasive CRC development in an epithelial-to-mesenchymal transition-prone tissue environment. Intestinal epithelial cell (IEC)-specific transgenic expression of the epithelial-to-mesenchymal transition regulator Zeb2 in mice (Zeb2^IEC-Tg/+) leads to increased intestinal permeability, myeloid cell-driven inflammation and spontaneous invasive CRC development. Zeb2^IEC-Tg/+ mice develop a dysplastic colonic epithelium, which progresses to severely inflamed neoplastic lesions while the small intestinal epithelium remains normal. Zeb2^IEC-Tg/+ mice are characterized by intestinal dysbiosis, and microbiota depletion with broad-spectrum antibiotics or germ-free rederivation completely prevents cancer development. Zeb2^IEC-Tg/+ mice represent the first mouse model of spontaneous microbiota-dependent invasive CRC and will help us to better understand host-microbiome interactions driving CRC development in humans.