Differentiation imbalance in single oesophageal progenitor cells causes clonal immortalization and field change

• Published in: Nature cell biology Vol. 16; no. 6; pp. 612 - 619
• Main Authors: Alcolea, Maria P., Greulich, Philip, Wabik, Agnieszka, Frede, Julia, Simons, Benjamin D., Jones, Philip H.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2014; Nature Publishing Group
• Subjects: 13/100; 14/19; 38/61; 631/67; 631/67/70; 64; 64/60; Animals; Cancer Research; Cell Biology; Cell cycle; Cell Differentiation; Cell Lineage; Cell Proliferation; Cell research; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Cellular signal transduction; Clone Cells; Cloning; Developmental Biology; Epithelial cells; Esophageal Neoplasms - genetics; Esophageal Neoplasms - metabolism; Esophageal Neoplasms - pathology; Esophagus - metabolism; Esophagus - pathology; Gene Expression Regulation, Neoplastic; Homeostasis; letter; Life Sciences; Medical research; Mice; Mice, Transgenic; Mutants; Mutation; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Physiological aspects; Proteins; Receptors, Notch - genetics; Receptors, Notch - metabolism; Stem Cells; Stem Cells - metabolism; Stem Cells - pathology; Time Factors; Transcription Factors - genetics; Transcription Factors - metabolism; United Kingdom > UK
• ISSN: 1465-7392; 1476-4679; 1476-4679
• DOI: 10.1038/ncb2963

Jones and colleagues combine lineage tracing experiments, chemical carcinogenesis assays and mathematical modelling to study field change development in a preneoplastic epithelium. They demonstrate that Notch pathway inhibition in oesophageal epithelial progenitor cells results in imbalanced differentiation, and mutant clone expansion and dominance in the epithelium, increasing the likelihood of transformation. Multiple cancers may arise from within a clonal region of preneoplastic epithelium, a phenomenon termed ‘field change’ 1 , 2 . 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 3 , 4 , 5 , 6 . 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.