Mutant clones in normal epithelium can limit the early formation of esophageal tumors in mice.

  • Major Finding: Mutant clones in normal epithelium can limit the early formation of esophageal tumors in mice.

  • Concept: Highly fit clones outcompete growth of emerging tumors and reduce the number of persisting lesions.

  • Impact: This study uncovers the novel tumor-suppressive role of mutant clones in normal epithelial tissue.

Epithelial tissues often acquire oncogenic mutations over time, but subsequent tumor formation remains relatively rare. These mutations in normal epithelial cells seem to undergo selection, leading Colom and colleagues to investigate whether the dynamics of competitive clones with enhanced fitness may affect the early stages of tumor formation. To examine the trajectory of premalignant tumors in a murine model of esophageal carcinogenesis, mice were administered the mutagen diethylnitrosamine (DEN) for 2 months, and esophagi were harvested at various time points up to 18 months following DEN withdrawal. After 10 days postwithdrawal, hundreds of small tumors were detected in each esophagus. Although individual tumors grew larger over time, the overall number of tumors rapidly decreased after several months. Targeted sequencing of genes implicated in epithelial carcinogenesis revealed that, although the overall spectrum of mutation types was similar between tumors harvested after 10 days and tumors harvested after 1 year, persisting tumors displayed genetic differences, with tumors after 10 days positively selecting for mutations in Notch1 and Trp53, whereas tumors after 1 year were enriched for mutations in Atp2a2, Notch1, Notch2, Chuk, and Adam10. Mechanistically, early tumor loss did not occur through apoptosis, decreased proliferation, or immune-mediated clearance, as immunostaining revealed no detectable activated caspase-3+ cells, no changes in EdU incorporation, or infiltration of immune cells. Notably, analysis of DEN-treated normal epithelium uncovered substantial numbers of mutant clones, displaying positive selection of Notch1, Trp53, and Fat1. To assess whether mutant clones could outcompete early tumors in the esophagus causing tumors to be extruded from the suprabasal surface of the epithelium, highly fit mutant clones were induced by expression of a dominant-negative allele of Maml-1, inhibiting Notch signaling. This resulted in a decrease in tumors observed 30 days post-DEN, with elimination of competitive advantage across the tissue via inhibition of Notch signaling reversing this decrease. In summary, this study demonstrates that the dynamics of mutant clonal selection in normal epithelium can play a tumor-suppressive role in early tumorigenesis.

Colom B, Herms A, Hall MWJ, Dentro SC, King C, Sood RK, et al. Mutant clones in normal epithelium outcompete and eliminate emerging tumors. Nature 2021;598:510–4.

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