NOTCH1 Mutations Inhibit Tumor Growth in the Esophageal Epithelium

Despite being frequently found in the aging normal esophageal epithelium, NOTCH1 mutant clones are relatively rarely present in esophageal cancers, suggesting that NOTCH1 mutations may suppress tumorigenesis. Abby and colleagues investigated the mechanism of NOTCH1 mutant clonal expansion and its impact on tissue maintenance and cancer growth in the esophageal epithelium and showed that, in the aging human esophagus, a majority of NOTCH1 mutant clones have biallelic alterations that disrupt signaling. Evaluation of how these NOTCH1 mutant clones colonize normal epithelium in transgenic mice revealed that the size of heterozygous Notch1 mutant (Notch1^+/‒) clones was larger than Notch1^+/+ cells, but the largest clones were formed by Notch1^‒/‒ cells. No differences in the cell division rate were observed between Notch1 mutant clones and wild-type clones, but the rate of differentiation and exit from the basal layer was reduced in Notch1^+/‒ and Notch1^‒/‒ clones, leading to more progenitors being produced after each cell division, while wild-type clones directly adjacent to Notch1^‒/‒ clones had greater differentiation and suprabasal migration, supporting the increased fitness of Notch1^+/‒ and Notch1^‒/‒ clones. Additionally, investigation into spontaneous Notch1 mutations that occur in aged mice indicated that Notch1 haploinsufficiency is critical for the colonization of the normal esophagus and the enhanced fitness of mutant clones. Interestingly, no phenotypic changes in the epithelium of aged Notch1^‒/‒ mice were observed, suggesting that mutant cells assume wild-type behavior once the epithelium is colonized. Furthermore, determination of the role of Notch1 in esophageal carcinogenesis showed that Notch1 mutations were not as ubiquitous in tumor tissue, but Notch1 deletion reduced tumor growth, while treatment with a NOTCH1 function-blocking antibody showed similar results. In summary, these results show that NOTCH1 mutations have differential effects in normal esophageal epithelium versus tumor tissue and suggest that investigation into NOTCH1 inhibitors for esophageal neoplasms is warranted.

Abby E, Dentro SC, Hall MWJ, Fowler JC, Ong SH, Sood R, et al. Notch1 mutations drive clonal expansion in normal esophageal epithelium but impair tumor growth. Nat Genet 2023 Jan 19 [Epub ahead of print].

Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.