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1. Spatial competition shapes the dynamic mutational landscape of normal esophageal epithelium

Author

Colom, Bartomeu, Alcolea, Maria P, Piedrafita, Gabriel, Hall, Michael WJ, Wabik, Agnieszka, Dentro, Stefan C, Fowler, Joanna C, Herms, Albert, King, Charlotte, Ong, Swee Hoe, Sood, Roshan K, Gerstung, Moritz, Martincorena, Inigo, Hall, Benjamin A, Jones, Philip H, Colom, Bartomeu [0000-0001-6256-6462], Piedrafita, Gabriel [0000-0001-8701-1084], Ong, Swee Hoe [0000-0002-3629-5387], Sood, Roshan K [0000-0002-1318-7025], Gerstung, Moritz [0000-0001-6709-963X], Hall, Benjamin A [0000-0003-0355-2946], Jones, Philip H [0000-0002-5904-795X], and Apollo - University of Cambridge Repository

Subjects
Male, High-Throughput Nucleotide Sequencing, Membrane Proteins, Reproducibility of Results, Mice, Transgenic, Epithelium, Mice, Inbred C57BL, ADAM10 Protein, Esophagus, Mutation, Animals, Cell Lineage, Diethylnitrosamine, Female, Receptor, Notch2, Amyloid Precursor Protein Secretases, Receptor, Notch1, Tumor Suppressor Protein p53, health care economics and organizations
Abstract

During aging, progenitor cells acquire mutations, which may generate clones that colonize the surrounding tissue. By middle age, normal human tissues, including the esophageal epithelium (EE), become a patchwork of mutant clones. Despite their relevance for understanding aging and cancer, the processes that underpin mutational selection in normal tissues remain poorly understood. Here, we investigated this issue in the esophageal epithelium of mutagen-treated mice. Deep sequencing identified numerous mutant clones with multiple genes under positive selection, including Notch1, Notch2 and Trp53, which are also selected in human esophageal epithelium. Transgenic lineage tracing revealed strong clonal competition that evolved over time. Clone dynamics were consistent with a simple model in which the proliferative advantage conferred by positively selected mutations depends on the nature of the neighboring cells. When clones with similar competitive fitness collide, mutant cell fate reverts towards homeostasis, a constraint that explains how selection operates in normal-appearing epithelium.

Published
2020

2. Spatial competition shapes the dynamic mutational landscape of normal esophageal epithelium

Author

Colom, Bartomeu, Alcolea, Maria P, Piedrafita, Gabriel, Hall, Michael WJ, Wabik, Agnieszka, Dentro, Stefan C, Fowler, Joanna C, Herms, Albert, King, Charlotte, Ong, Swee Hoe, Sood, Roshan K, Gerstung, Moritz, Martincorena, Inigo, Hall, Benjamin A, and Jones, Philip H

Subjects
Male, High-Throughput Nucleotide Sequencing, Membrane Proteins, Reproducibility of Results, Mice, Transgenic, Epithelium, 3. Good health, Mice, Inbred C57BL, ADAM10 Protein, Esophagus, Mutation, Animals, Cell Lineage, Diethylnitrosamine, Female, Receptor, Notch2, Amyloid Precursor Protein Secretases, Receptor, Notch1, Tumor Suppressor Protein p53
Abstract

During aging, progenitor cells acquire mutations, which may generate clones that colonize the surrounding tissue. By middle age, normal human tissues, including the esophageal epithelium (EE), become a patchwork of mutant clones. Despite their relevance for understanding aging and cancer, the processes that underpin mutational selection in normal tissues remain poorly understood. Here, we investigated this issue in the esophageal epithelium of mutagen-treated mice. Deep sequencing identified numerous mutant clones with multiple genes under positive selection, including Notch1, Notch2 and Trp53, which are also selected in human esophageal epithelium. Transgenic lineage tracing revealed strong clonal competition that evolved over time. Clone dynamics were consistent with a simple model in which the proliferative advantage conferred by positively selected mutations depends on the nature of the neighboring cells. When clones with similar competitive fitness collide, mutant cell fate reverts towards homeostasis, a constraint that explains how selection operates in normal-appearing epithelium.

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