Biology subjects

Abby, E.

Publications and source records attributed to Abby, E..

3 recordsLinked to original sources

bioRxiv2024

Somatic mutant selection is altered by prior NOTCH1 mutation in aging esophageal epithelium

The ageing mid esophagus is progressively colonized by somatic mutations, including oncogenic TP53 and antioncogenic NOTCH1 mutants. Most esophageal squamous carcinomas are TP53 mutant, NOTCH1 wild type. By middle age, much of the esophagus is NOTCH1 mutant. We hypothesised that prior NOTCH1 mutation may alter subsequent mutant selection. Here we show that selection of mutant NOTCH2 was increased and mutant TP53 decreased within NOTCH1 mutant epithelium. Potential mechanisms include spatial competition between adjacent clones and/or epistasis altering the fitness NOTCH1 double mutants. We investigated these possibilities in transgenic mice. Spontaneous Notch2 mutant clones emerged in aged Notch1 null, but not wild type, esophagus, consistent with epistasis increasing Notch1/Notch2 double mutant fitness. However, there was no evidence of epistasis between Notch1 and Trp53, as Notch1 mutation alone increased fitness. In consequence, over time, Trp53 mutant Notch1 wild type clones were outcompeted by expanding Notch1 and Trp53/Notch1 mutants. NOTCH1 mutant takeover of the aging esophagus alters the trajectory of somatic evolution, decreasing selection of TP53 mutants and potentially reducing cancer risk.

genomics↗

bioRxiv2023

Epithelioids: Self-sustaining 3D epithelial cultures to study long-term processes

Studying long-term biological processes such as the colonization of aging epithelia by somatic mutant clones has been slowed by the lack of suitable culture systems. Here we describe epithelioids, a facile, cost-effective method of culturing multiple mouse and human epithelia. Esophageal epithelioids self-maintain without passaging for at least a year, recapitulating the 3D structure, cell dynamics, transcriptome, and genomic stability of the esophagus. Live imaging over 5 months showed epithelioids replicate in vivo cell dynamics. Epithelioids enable the study of cell competition and mutant selection in 3D epithelia, and how anti-cancer treatments modulate the competition between transformed and wild type cells. Epithelioids are a novel method with a wide range of applications in epithelial tissues, particularly the study of long term processes, that cannot be accessed using other culture models.

cell biology↗

bioRxiv2021

Notch1 mutation drives clonal expansion in normal esophageal epithelium but impairs tumor growth

NOTCH1 mutant clones occupy the majority of normal human esophagus by middle age, but are comparatively rare in esophageal cancers, suggesting NOTCH1 mutations may promote clonal expansion but impede carcinogenesis1-3. Here we test this hypothesis. Visualizing and sequencing NOTCH1 mutant clones in aging normal human esophagus reveals frequent biallelic mutations that block NOTCH1 signaling. In mouse esophagus, heterozygous Notch1 mutation confers a competitive advantage over wild type cells, an effect enhanced by loss of the second allele. Notch1 loss alters transcription but has minimal effects on epithelial structure and cell dynamics. In a carcinogenesis model, Notch1 mutations were less prevalent in tumors than normal epithelium. Deletion of Notch1 reduced tumor growth, an effect recapitulated by anti-NOTCH1 antibody treatment. We conclude that Notch1 mutations in normal epithelium are beneficial as wild type Notch1 promotes tumor expansion. NOTCH1 blockade may have therapeutic potential in preventing esophageal squamous cancer.

cancer biology↗