Bone morphogenetic protein and Notch signalling crosstalk in poor-prognosis, mesenchymal-subtype colorectal cancer

Research output: Contribution to journalArticle

Authors

  • Shazia Irshad
  • Mukesh Bansal
  • Paolo Guarnieri
  • Hayley Davis
  • Ayman Al Haj Zen
  • Brygida Baran
  • Claudia Maria Assunta Pinna
  • Haseeb Rahman
  • Sujata Biswas
  • Rosemary Jeffery
  • Lai Mun Wang
  • James Edward East
  • Ian Tomlinson
  • Annabelle Lewis
  • Simon John Leedham

Colleges, School and Institutes

External organisations

  • Gastrointestinal Stem-cell Biology Laboratory, Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
  • PsychoGenics Inc., 765 Old Saw Mill River Road, Tarrytown, NY, USA.
  • Department of Systems Biology, Columbia University Medical Center, New York, NY, USA.
  • From the Division of Cardiovascular Medicine, British Heart Foundation Centre for Research Excellence, Radcliffe Department of Medicine, John Radcliffe Hospital, United Kingdom (E.M., D.J., J.P., P.C., K.M.C.); Wellcome Trust Centre for Human Genetics, Headington, Oxford, United Kingdom (E.M., J.P., P.C., K.M.C.); and Sir William Dunn School of Pathology, University of Oxford, United Kingdom (A.J.I., L.T., D.R.G.). eileen.mcneill@well.ox.ac.uk.
  • Department of Genetics, Faculty of Biology and Environmental Protection, University of Silesia, Katowice, Poland.
  • Department of Surgery, Oncology and Gastroenterology, University Hospital Padova, Padova, Italy.
  • Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, UK.
  • Molecular and Population Genetics Laboratory, Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.
  • Colorectal Cancer Genetics, Centre for Digestive Diseases, Blizard Institute, Barts and the London School of Medicine and Dentistry, 4 Newark Street, Whitechapel, London, E1 2AT, UK.
  • Cellular Pathology, Level 1, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK.
  • Translational Gastroenterology Unit, Experimental Medicine Division, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK.

Abstract

The functional role of bone morphogenetic protein (BMP) signalling in colorectal cancer (CRC) is poorly defined, with contradictory results in cancer cell line models reflecting the inherent difficulties of assessing a signalling pathway that is context-dependent and subject to genetic constraints. By assessing the transcriptional response of a diploid human colonic epithelial cell line to BMP ligand stimulation, we generated a prognostic BMP signalling signature, which was applied to multiple CRC datasets to investigate BMP heterogeneity across CRC molecular subtypes. We linked BMP and Notch signalling pathway activity and function in human colonic epithelial cells, and normal and neoplastic tissue. BMP induced Notch through a γ-secretase-independent interaction, regulated by the SMAD proteins. In homeostasis, BMP/Notch co-localization was restricted to cells at the top of the intestinal crypt, with more widespread interaction in some human CRC samples. BMP signalling was downregulated in the majority of CRCs, but was conserved specifically in mesenchymal-subtype tumours, where it interacts with Notch to induce an epithelial-mesenchymal transition (EMT) phenotype. In intestinal homeostasis, BMP-Notch pathway crosstalk is restricted to differentiating cells through stringent pathway segregation. Conserved BMP activity and loss of signalling stringency in mesenchymal-subtype tumours promotes a synergistic BMP-Notch interaction, and this correlates with poor patient prognosis. BMP signalling heterogeneity across CRC subtypes and cell lines can account for previous experimental contradictions. Crosstalk between the BMP and Notch pathways will render mesenchymal-subtype CRC insensitive to γ-secretase inhibition unless BMP activation is concomitantly addressed. © 2017 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Details

Original languageEnglish
Pages (from-to)178-192
Number of pages15
JournalJournal of Pathology
Volume242
Issue number2
Early online date3 May 2017
Publication statusPublished - Jun 2017

Keywords

  • Amyloid Precursor Protein Secretases/genetics, Bone Morphogenetic Proteins/genetics, Cell Differentiation, Cohort Studies, Colorectal Neoplasms/diagnosis, Epithelial Cells/pathology, Epithelial-Mesenchymal Transition, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Kaplan-Meier Estimate, Models, Biological, Phenotype, Prognosis, Receptors, Notch/genetics, Signal Transduction, Smad Proteins/genetics