Biased competition between Lgr5 intestinal stem cells driven by oncogenic mutation induces clonal expansion

• Published in: EMBO reports 2014-01, Vol.15 (1), p.62-69
• Main Authors: Snippert, Hugo J., Schepers, Arnout G., van Es, Johan H., Simons, Benjamin D., Clevers, Hans
• Format: Article
• Language: English
• Subjects: Adult Stem Cells - physiology; Animals; Cell Cycle; Cell division; Cell Proliferation; Cell Transformation, Neoplastic; Cloning; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Competition; crypt fission; EMBO03; EMBO39; field cancerization; Intestinal Mucosa - pathology; Intestine, Small - pathology; K-ras; Lgr5 intestinal stem cells; Mice; Mice, Transgenic; Mutation; Mutation, Missense; neutral competition; Oncogenes; Oncology; Proto-Oncogene Proteins p21(ras) - genetics; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Scientific Report; Scientific Reports; Stem Cell Niche; Stem cells
• ISSN: 1469-221X; 1469-3178
• DOI: 10.1002/embr.201337799

The concept of ‘field cancerization’ describes the clonal expansion of genetically altered, but morphologically normal cells that predisposes a tissue to cancer development. Here, we demonstrate that biased stem cell competition in the mouse small intestine can initiate the expansion of such clones. We quantitatively analyze how the activation of oncogenic K‐ras in individual Lgr5 + stem cells accelerates their cell division rate and creates a biased drift towards crypt clonality. K‐ras mutant crypts then clonally expand within the epithelium through enhanced crypt fission, which distributes the existing Paneth cell niche over the two new crypts. Thus, an unequal competition between wild‐type and mutant intestinal stem cells initiates a biased drift that leads to the clonal expansion of crypts carrying oncogenic mutations. Synopsis The fate of normal intestinal stem cells is determined through neutral competition. This study shows that when oncogenic K‐Ras mutations arise, biased stem cell competition leads to a drift towards mutant crypt expansion that could be the underlying cause of field cancerization. Lgr5+ intestinal stem cells obtain a competitive advantage by oncogenic K‐ras mutations Unequal stem cell competition will induce a biased drift towards crypt clonality Cancer prone mutations can clonally expand by crypt fission Graphical Abstract The fate of normal intestinal stem cells is determined through neutral competition. This study shows that when oncogenic K‐Ras mutations arise, biased stem cell competition leads to a drift towards mutant crypt expansion that could be the underlying cause of field cancerization.