Universität zu Köln

Fessler, Evelyn, Drost, Jarno ORCID: 0000-0002-2941-6179, van Hooff, Sander R., Linnekamp, Janneke F., Wang, Xin ORCID: 0000-0002-5122-2418, Jansen, Marnix, Melo, Felipe De Sousa E., Prasetyanti, Pramudita R., Ijspeert, Joep E. G., Franitza, Marek, Nurnberg, Peter, van Noesel, Carel J. M., Dekker, Evelien, Vermeulen, Louis ORCID: 0000-0002-6066-789X, Clevers, Hans and Medema, Jan Paul (2016). TGF beta signaling directs serrated adenomas to the mesenchymal colorectal cancer subtype. EMBO Mol. Med., 8 (7). S. 745 - 761. HOBOKEN: WILEY. ISSN 1757-4684

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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 TGF beta 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 TGF beta is death by apoptosis. By contrast, induction of a mesenchymal phenotype upon TGF beta treatment prevails in a genetically engineered organoid culture carrying a BRAFV600E mutation, constituting a model system for sessile serrated adenomas (SSAs). Our data indicate that TGF beta signaling is already active in SSA precursor lesions and that TGF beta is a critical cue for directing SSAs to the mesenchymal, poor-prognosis CMS4 of CRC.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Fessler, Evelyn UNSPECIFIED UNSPECIFIED UNSPECIFIED Drost, Jarno UNSPECIFIED orcid.org/0000-0002-2941-6179 UNSPECIFIED van Hooff, Sander R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Linnekamp, Janneke F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wang, Xin UNSPECIFIED orcid.org/0000-0002-5122-2418 UNSPECIFIED Jansen, Marnix UNSPECIFIED UNSPECIFIED UNSPECIFIED Melo, Felipe De Sousa E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Prasetyanti, Pramudita R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ijspeert, Joep E. G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Franitza, Marek UNSPECIFIED UNSPECIFIED UNSPECIFIED Nurnberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED van Noesel, Carel J. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dekker, Evelien UNSPECIFIED UNSPECIFIED UNSPECIFIED Vermeulen, Louis UNSPECIFIED orcid.org/0000-0002-6066-789X UNSPECIFIED Clevers, Hans UNSPECIFIED UNSPECIFIED UNSPECIFIED Medema, Jan Paul UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-270202
DOI:	10.15252/emmm.201606184
Journal or Publication Title:	EMBO Mol. Med.
Volume:	8
Number:	7
Page Range:	S. 745 - 761
Date:	2016
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1757-4684
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MOLECULAR SUBTYPES; POOR SURVIVAL; HUMAN COLON; EXPRESSION; METASTASIS; TRANSITION; APOPTOSIS; GROWTH; CELLS; METHYLATION Multiple languages Medicine, Research & Experimental Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/27020