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

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Bone morphogenetic protein and Notch signalling crosstalk in poor-prognosis, mesenchymal-subtype colorectal cancer. / Irshad, Shazia; Bansal, Mukesh; Guarnieri, Paolo; Davis, Hayley; Al Haj Zen, Ayman; Baran, Brygida; Pinna, Claudia Maria Assunta; Rahman, Haseeb; Biswas, Sujata; Bardella, Chiara; Jeffery, Rosemary; Wang, Lai Mun; East, James Edward; Tomlinson, Ian; Lewis, Annabelle; Leedham, Simon John.

In: Journal of Pathology, Vol. 242, No. 2, 06.2017, p. 178-192.

Research output: Contribution to journalArticlepeer-review

Harvard

Irshad, S, Bansal, M, Guarnieri, P, Davis, H, Al Haj Zen, A, Baran, B, Pinna, CMA, Rahman, H, Biswas, S, Bardella, C, Jeffery, R, Wang, LM, East, JE, Tomlinson, I, Lewis, A & Leedham, SJ 2017, 'Bone morphogenetic protein and Notch signalling crosstalk in poor-prognosis, mesenchymal-subtype colorectal cancer', Journal of Pathology, vol. 242, no. 2, pp. 178-192. https://doi.org/10.1002/path.4891

APA

Irshad, S., Bansal, M., Guarnieri, P., Davis, H., Al Haj Zen, A., Baran, B., Pinna, C. M. A., Rahman, H., Biswas, S., Bardella, C., Jeffery, R., Wang, L. M., East, J. E., Tomlinson, I., Lewis, A., & Leedham, S. J. (2017). Bone morphogenetic protein and Notch signalling crosstalk in poor-prognosis, mesenchymal-subtype colorectal cancer. Journal of Pathology, 242(2), 178-192. https://doi.org/10.1002/path.4891

Vancouver

Author

Irshad, Shazia ; Bansal, Mukesh ; Guarnieri, Paolo ; Davis, Hayley ; Al Haj Zen, Ayman ; Baran, Brygida ; Pinna, Claudia Maria Assunta ; Rahman, Haseeb ; Biswas, Sujata ; Bardella, Chiara ; Jeffery, Rosemary ; Wang, Lai Mun ; East, James Edward ; Tomlinson, Ian ; Lewis, Annabelle ; Leedham, Simon John. / Bone morphogenetic protein and Notch signalling crosstalk in poor-prognosis, mesenchymal-subtype colorectal cancer. In: Journal of Pathology. 2017 ; Vol. 242, No. 2. pp. 178-192.

Bibtex

@article{4c37ef16380a47828e22efe62e5f4d0c,
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. {\textcopyright} 2017 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.",
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",
author = "Shazia Irshad and Mukesh Bansal and Paolo Guarnieri and Hayley Davis and {Al Haj Zen}, Ayman and Brygida Baran and Pinna, {Claudia Maria Assunta} and Haseeb Rahman and Sujata Biswas and Chiara Bardella and Rosemary Jeffery and Wang, {Lai Mun} and East, {James Edward} and Ian Tomlinson and Annabelle Lewis and Leedham, {Simon John}",
note = "{\textcopyright} 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.",
year = "2017",
month = jun,
doi = "10.1002/path.4891",
language = "English",
volume = "242",
pages = "178--192",
journal = "Journal of Pathology",
issn = "0022-3417",
publisher = "Wiley",
number = "2",

}

RIS

TY - JOUR

T1 - Bone morphogenetic protein and Notch signalling crosstalk in poor-prognosis, mesenchymal-subtype colorectal cancer

AU - Irshad, Shazia

AU - Bansal, Mukesh

AU - Guarnieri, Paolo

AU - Davis, Hayley

AU - Al Haj Zen, Ayman

AU - Baran, Brygida

AU - Pinna, Claudia Maria Assunta

AU - Rahman, Haseeb

AU - Biswas, Sujata

AU - Bardella, Chiara

AU - Jeffery, Rosemary

AU - Wang, Lai Mun

AU - East, James Edward

AU - Tomlinson, Ian

AU - Lewis, Annabelle

AU - Leedham, Simon John

N1 - © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

PY - 2017/6

Y1 - 2017/6

N2 - 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.

AB - 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.

KW - Amyloid Precursor Protein Secretases/genetics

KW - Bone Morphogenetic Proteins/genetics

KW - Cell Differentiation

KW - Cohort Studies

KW - Colorectal Neoplasms/diagnosis

KW - Epithelial Cells/pathology

KW - Epithelial-Mesenchymal Transition

KW - Gene Expression Profiling

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Kaplan-Meier Estimate

KW - Models, Biological

KW - Phenotype

KW - Prognosis

KW - Receptors, Notch/genetics

KW - Signal Transduction

KW - Smad Proteins/genetics

U2 - 10.1002/path.4891

DO - 10.1002/path.4891

M3 - Article

C2 - 28299802

VL - 242

SP - 178

EP - 192

JO - Journal of Pathology

JF - Journal of Pathology

SN - 0022-3417

IS - 2

ER -