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

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.

Cited by papers we hold 8

• Stem cells in homeostasis and cancer of the gut · 2019
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• Functional robustness of adult spermatogonial stem cells after induction of hyperactive Hras. · 2019
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• Colorectal Cancer: Genetic Abnormalities, Tumor Progression, Tumor Heterogeneity, Clonal Evolution and Tumor-Initiating Cells · 2018
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• Wnt Signaling in Cancer Stem Cell Biology · 2016
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• Cell Competition Drives the Growth of Intestinal Adenomas in Drosophila · 2016
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• Targeting mutant RAS in patient-derived colorectal cancer organoids by combinatorial drug screening · 2016
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• The molecular clock of neutral evolution can be accelerated or slowed by asymmetric spatial structure. · 2015
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• Similar but different: distinct roles for KRAS and BRAF oncogenes in colorectal cancer development and therapy resistance · 2015
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