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TGFβ signaling directs serrated adenomas to the mesenchymal colorectal cancer subtype.

Fessler, E; Drost, J; van Hooff, SR; Linnekamp, JF; Wang, X; Jansen, M; De Sousa E Melo, F; ... Medema, JP; + view all (2016) TGFβ signaling directs serrated adenomas to the mesenchymal colorectal cancer subtype. EMBO Molecular Medicine , 8 (7) pp. 745-760. 10.15252/emmm.201606184. Green open access

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Abstract

The heterogeneous nature of colorectal cancer (CRC) complicates prognosis and is suggested to be a determining factor in the efficacy of adjuvant therapy for individual patients. Based on gene expression profiling, CRC is currently classified into four consensus molecular subtypes (CMSs), characterized by specific biological programs, thus suggesting the existence of unifying developmental drivers for each CMS Using human organoid cultures, we investigated the role of such developmental drivers at the premalignant stage of distinct CRC subtypes and found that TGFβ plays an important role in the development of the mesenchymal CMS4, which is of special interest due to its association with dismal prognosis. We show that in tubular adenomas (TAs), which progress to classical CRCs, the dominating response to TGFβ is death by apoptosis. By contrast, induction of a mesenchymal phenotype upon TGFβ treatment prevails in a genetically engineered organoid culture carrying a BRAF(V) (600E) mutation, constituting a model system for sessile serrated adenomas (SSAs). Our data indicate that TGFβ signaling is already active in SSA precursor lesions and that TGFβ is a critical cue for directing SSAs to the mesenchymal, poor-prognosis CMS4 of CRC.

Type: Article
Title: TGFβ signaling directs serrated adenomas to the mesenchymal colorectal cancer subtype.
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.15252/emmm.201606184
Publisher version: http://dx.doi.org/10.15252/emmm.201606184
Language: English
Additional information: Copyright © 2016 The Authors. Published under the terms of the CC BY 4.0 license.
Keywords: Cancer Subtypes, Colorectal Cancer, Epithelial–Mesenchymal Transition, Sessile Serrated Adenoma, Transforming Growth Factor Beta (TGFβ)
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Pathology
URI: http://discovery.ucl.ac.uk/id/eprint/10047010
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