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

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

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)
133 Downloads (Pure)

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.

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

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