title: Differentiation imbalance in single oesophageal progenitor cells causes clonal immortalization and field change.
abstract: Multiple cancers may arise from within a clonal region of preneoplastic epithelium, a phenomenon termed 'field change'. However, it is not known how field change develops. Here we investigate this question using lineage tracing to track the behaviour of scattered single oesophageal epithelial progenitor cells expressing a mutation that inhibits the Notch signalling pathway. Notch is frequently subject to inactivating mutation in squamous cancers. Quantitative analysis reveals that cell divisions that produce two differentiated daughters are absent from mutant progenitors. As a result, mutant clones are no longer lost by differentiation and become functionally immortal. Furthermore, mutant cells promote the differentiation of neighbouring wild-type cells, which are then lost from the tissue. These effects lead to clonal expansion, with mutant cells eventually replacing the entire epithelium. Notch inhibition in progenitors carrying p53 stabilizing mutations creates large confluent regions of doubly mutant epithelium. Field change is thus a consequence of imbalanced differentiation in individual progenitor cells.
authors.affiliation: MRC Cancer Unit, University of Cambridge, Hutchison-MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK.
authors.forename: Maria P
authors.initials: MP
authors.lastname: Alcolea
authors.affiliation: Cavendish Laboratory, Department of Physics, University of Cambridge, J.J. Thomson Avenue, Cambridge CB3 0HE, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Greulich
authors.affiliation: MRC Cancer Unit, University of Cambridge, Hutchison-MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Wabik
authors.affiliation: MRC Cancer Unit, University of Cambridge, Hutchison-MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK.
authors.forename: Julia
authors.initials: J
authors.lastname: Frede
authors.affiliation: 1] Cavendish Laboratory, Department of Physics, University of Cambridge, J.J. Thomson Avenue, Cambridge CB3 0HE, UK [2] The Wellcome Trust-Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK [3] Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge CB2 1QN, UK.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Simons
authors.affiliation: MRC Cancer Unit, University of Cambridge, Hutchison-MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK.
authors.forename: Philip H
authors.initials: PH
authors.lastname: Jones
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002999:Clone Cells; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004947:Esophagus / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology*; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C486455:Maml1 protein, mouse; D009687:Nuclear Proteins; D051880:Receptors, Notch; D014157:Transcription Factors