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

Area of Science:

• Gastroenterology
• Oncology
• Stem Cell Biology

Background:

• Field cancerization involves the expansion of genetically altered cells, predisposing tissue to cancer.
• Intestinal stem cells (Lgr5(+) cells) are crucial for maintaining gut epithelium homeostasis.

Purpose of the Study:

• To investigate how biased stem cell competition initiates field cancerization in the mouse small intestine.
• To elucidate the role of oncogenic K-ras activation in driving clonal expansion of intestinal stem cells.

Main Methods:

• Quantitative analysis of Lgr5(+) stem cell division rates in response to oncogenic K-ras activation.
• Modeling crypt fission dynamics and Paneth cell niche distribution.
• Tracking clonal expansion within the intestinal epithelium.

Main Results:

• Activation of oncogenic K-ras in individual stem cells accelerates their division rate.
• This leads to a biased drift towards crypt clonality.
• Mutant crypts expand via enhanced crypt fission, effectively distributing the Paneth cell niche.

Conclusions:

• Unequal competition between wild-type and mutant intestinal stem cells initiates a biased drift.
• This process results in the clonal expansion of crypts harboring oncogenic mutations, a key step in field cancerization.