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

TY - JOUR

T1 - Biased competition between Lgr5 intestinal stem cells driven by oncogenic mutation induces clonal expansion

AU - Snippert, Hugo J

AU - Schepers, Arnout G

AU - van Es, Johan H

AU - Simons, Benjamin D

AU - Clevers, Hans

PY - 2014/1

Y1 - 2014/1

N2 - 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.

AB - 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.

KW - Adult Stem Cells

KW - Animals

KW - Cell Cycle

KW - Cell Proliferation

KW - Cell Transformation, Neoplastic

KW - Colorectal Neoplasms

KW - Intestinal Mucosa

KW - Intestine, Small

KW - Mice

KW - Mice, Transgenic

KW - Mutation, Missense

KW - Oncogenes

KW - Proto-Oncogene Proteins p21(ras)

KW - Receptors, G-Protein-Coupled

KW - Stem Cell Niche

U2 - 10.1002/embr.201337799

DO - 10.1002/embr.201337799

M3 - Article

C2 - 24355609

SN - 1469-221X

VL - 15

SP - 62

EP - 69

JO - EMBO Reports

JF - EMBO Reports

IS - 1

ER -