title: Bone morphogenetic protein and Notch signalling crosstalk in poor-prognosis, mesenchymal-subtype colorectal cancer.
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.
authors.affiliation: Gastrointestinal Stem-cell Biology Laboratory, Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Shazia
authors.initials: S
authors.lastname: Irshad
authors.affiliation: Department of Systems Biology, Columbia University Medical Center, New York, NY, USA.|PsychoGenics Inc., 765 Old Saw Mill River Road, Tarrytown, NY, USA.
authors.forename: Mukesh
authors.initials: M
authors.lastname: Bansal
authors.affiliation: Department of Systems Biology, Columbia University Medical Center, New York, NY, USA.
authors.forename: Paolo
authors.initials: P
authors.lastname: Guarnieri
authors.affiliation: Gastrointestinal Stem-cell Biology Laboratory, Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Hayley
authors.initials: H
authors.lastname: Davis
authors.affiliation: Wellcome Trust Centre For Human Genetics, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Ayman
authors.initials: A
authors.lastname: Al Haj Zen
authors.affiliation: Department of Genetics, Faculty of Biology and Environmental Protection, University of Silesia, Katowice, Poland.
authors.forename: Brygida
authors.initials: B
authors.lastname: Baran
authors.affiliation: Gastrointestinal Stem-cell Biology Laboratory, Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.|Department of Surgery, Oncology and Gastroenterology, University Hospital Padova, Padova, Italy.
authors.forename: Claudia Maria Assunta
authors.initials: CMA
authors.lastname: Pinna
authors.affiliation: Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, UK.
authors.forename: Haseeb
authors.initials: H
authors.lastname: Rahman
authors.affiliation: Gastrointestinal Stem-cell Biology Laboratory, Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Sujata
authors.initials: S
authors.lastname: Biswas
authors.affiliation: Molecular and Population Genetics Laboratory, Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Chiara
authors.initials: C
authors.lastname: Bardella
authors.affiliation: Colorectal Cancer Genetics, Centre for Digestive Diseases, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, UK.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Jeffery
authors.affiliation: Cellular Pathology, Level 1, John Radcliffe Hospital, Oxford, UK.
authors.forename: Lai Mun
authors.initials: LM
authors.lastname: Wang
authors.affiliation: Translational Gastroenterology Unit, Experimental Medicine Division, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford, UK.
authors.forename: James Edward
authors.initials: JE
authors.lastname: East
authors.affiliation: Molecular and Population Genetics Laboratory, Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
authors.affiliation: Molecular and Population Genetics Laboratory, Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Annabelle
authors.initials: A
authors.lastname: Lewis
authors.affiliation: Gastrointestinal Stem-cell Biology Laboratory, Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.|Translational Gastroenterology Unit, Experimental Medicine Division, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford, UK.
authors.forename: Simon John
authors.initials: SJ
authors.lastname: Leedham
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D004847:Epithelial Cells / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008954:Models, Biological; D010641:Phenotype; D011379:Prognosis; D051880:Receptors, Notch / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; D051880:Receptors, Notch; D051785:Smad Proteins; D053829:Amyloid Precursor Protein Secretases
keywords: BMP; EMT; Notch; colorectal cancer subtypes