Using the DEN carcinogenesis model, Skrupskelyte and Arias et al. showed that early tumor persistence depended on the formation of a fibrotic precancerous niche. Stress responses in nascent epithelial lesions activated EGFR signaling, induced SOX9⁺, recruited PDGFRαlow fibroblasts, and drove the formation of a fibronectin (FN1)-rich niche that promoted tumor growth. Tumor-derived stroma alone was sufficient to impose tumor traits in normal epithelium. Inhibition of either fibronectin fibrillogenesis or EGFR signaling prevented niche formation and reduced tumor burdens. Heterogeneous AREG+ (an EGF ligand) and/or SOX9+ populations were present in early human oesophageal carcinoma.
Contributed by Shishir Pant
ABSTRACT: Interactions between mutant cells and their environment have a key role in determining cancer susceptibility(1-3). However, understanding of how the precancerous microenvironment contributes to early tumorigenesis remains limited. Here we show that newly emerging tumours at their most incipient stages shape their microenvironment in a critical process that determines their survival. Analysis of nascent squamous tumours in the upper gastrointestinal tract of the mouse reveals that the stress response of early tumour cells instructs the underlying mesenchyme to form a supportive 'precancerous niche', which dictates the long-term outcome of epithelial lesions. Stimulated fibroblasts beneath emerging tumours activate a wound-healing response that triggers a marked remodelling of the underlying extracellular matrix, resulting in the formation of a fibronectin-rich stromal scaffold that promotes tumour growth. Functional heterotypic 3D culture assays and in vivo grafting experiments, combining carcinogen-free healthy epithelium and tumour-derived stroma, demonstrate that the precancerous niche alone is sufficient to confer tumour properties to normal epithelial cells. We propose a model in which both mutations and the stromal response to genetic stress together define the likelihood of early tumours to persist and progress towards more advanced disease stages.
Author Info: (1) Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK. gs463@cam.ac.uk. Department of Physiology, Development and Neuroscience,
Author Info: (1) Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK. gs463@cam.ac.uk. Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK. gs463@cam.ac.uk. (2) Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK. Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK. RhyGaze, Basel, Switzerland. (3) Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK. Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK. (4) Max Planck Institute for Molecular Cell Biology and Genetics, Dresden, Germany. Max Planck Institute for the Physics of Complex Systems, Dresden, Germany. Center for Systems Biology, Dresden, Germany. (5) Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK. Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK. (6) Gurdon Institute, University of Cambridge, Cambridge, UK. (7) Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK. Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK. (8) Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK. Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK. (9) Wellcome Sanger Institute, Hinxton, UK. Cambridge Institute of Science, Altos Labs, Cambridge, UK. (10) Wellcome Sanger Institute, Hinxton, UK. (11) Wellcome Sanger Institute, Hinxton, UK. (12) Wellcome Sanger Institute, Hinxton, UK. (13) University Hospital Carl Gustav Carus Dresden, Faculty of Medicine of TUD Dresden University of Technology, Dresden, Germany. Institute of Pathology, University Hospital CGC Dresden, TU Dresden, Dresden, Germany. (14) Institute of Anatomy, Faculty of Medicine of TUD, University of Technology, Dresden, Germany. (15) Institute of Anatomy, Faculty of Medicine of TUD, University of Technology, Dresden, Germany. (16) Department of Gastroenterology, Guy's and St. Thomas' Hospital, London, UK. (17) Wellcome Sanger Institute, Hinxton, UK. Addenbrooke's Hospital, Cambridge University Hospital NHS Trust, Cambridge, UK. (18) Wellcome Sanger Institute, Hinxton, UK. Department of Oncology, University of Cambridge, Hutchison Research Centre, Cambridge Biomedical Campus, Cambridge, UK. (19) Max Planck Institute for the Physics of Complex Systems, Dresden, Germany. Arnold Sommerfeld Center for Theoretical Physics, Ludwigs-Maximilians-Universitt Munchen, Munich, Germany. (20) Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK. Gurdon Institute, University of Cambridge, Cambridge, UK. Department of Applied Mathematics and Theoretical Physics, Centre for Mathematical Science, University of Cambridge, Cambridge, UK. (21) Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK. mpa28@cam.ac.uk. Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK. mpa28@cam.ac.uk.
