Premium
Biased competition between Lgr5 intestinal stem cells driven by oncogenic mutation induces clonal expansion
Author(s) -
Snippert Hugo J.,
Schepers Arnout G.,
Es Johan H.,
Simons Benjamin D.,
Clevers Hans
Publication year - 2014
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1002/embr.201337799
Subject(s) - biology , lgr5 , stem cell , crypt , paneth cell , microbiology and biotechnology , mutant , intestinal epithelium , genetics , cell division , cancer stem cell , cancer research , cell , epithelium , gene , small intestine , biochemistry , endocrinology
Abstract 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.