Cell fate imbalance in the Oesophageal Epithelium: mutant cell competition


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Maria Alcolea1
1Wellcome Trust-MRC Cambridge Stem Cell Institute

Abstract

Background

Notch signalling pathway is of significant importance for cell fate determination in several systems, and has been linked to cancer development including squamous oesophageal carcinogenesis. However, the role of Notch in oesophageal progenitor cell behaviour still remains largely unknown. We have previously reported how the squamous epithelium of the mouse oesophagus is maintained and repaired by a functionally equivalent progenitor population.

Method

To investigate how Notch may regulate such cell fate decisions, we expressed a dominant negative form of mastermind-like mutant fused to GFP, which blocks canonical Notch signalling of oesophageal epithelial progenitors at single cell resolution in the mouse oesophagus. Lineage tracing of GFP labelled single cell derived clones was performed to unveil mutant cell dynamics. 

Results

Analysis of labelled clone data over one year time course reveals a significant alteration in mutant cell behaviour. The results indicate that mutant clones expand over time due to accelerated cell proliferation, together with a selective block of terminal divisions. Additionally, activation of Notch signalling in adjacent non-mutant cells accelerates their stratification at the clone boundary, promoting clonal expansion. The latter explains how mutant clones progressively take over the entire oesophageal epithelium over one year period.

Conclusion

Our observations suggest that loss of function Notch mutations confer clonal dominance, leading to clonal immortalization and field change. As a result, Notch inhibition increases the number and size of tumours that develop following carcinogen treatment. These observations illustrate that, as well as cooperating at the molecular level within cells, oncogenic mutations may also interact at the level of cell dynamics in early cancer evolution.