TGFβ signaling directs serrated adenomas to the mesenchymal colorectal cancer subtype

Evelyn Fessler, Jarno Drost, Sander R van Hooff, Janneke F Linnekamp, Xin Wang, Marnix Jansen, Felipe De Sousa E Melo, Pramudita R Prasetyanti, Joep Eg IJspeert, Marek Franitza, Peter Nürnberg, Carel Jm van Noesel, Evelien Dekker, Louis Vermeulen, Hans Clevers, Jan Paul Medema

Research output: Contribution to journal/periodicalArticleScientificpeer-review

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.

Original languageEnglish
Pages (from-to)745-60
Number of pages16
JournalEMBO Molecular Medicine
Volume8
Issue number7
DOIs
Publication statusPublished - 2016

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