TY - JOUR
T1 - TGFβ signaling directs serrated adenomas to the mesenchymal colorectal cancer subtype
AU - Fessler, Evelyn
AU - Drost, Jarno
AU - van Hooff, Sander R.
AU - Linnekamp, Janneke F.
AU - Wang, Xin
AU - Jansen, Marnix
AU - de Sousa E Melo, Felipe
AU - Prasetyanti, Pramudita R.
AU - IJspeert, Joep Eg
AU - Franitza, Marek
AU - Nürnberg, Peter
AU - van Noesel, Carel Jm
AU - Dekker, Evelien
AU - Vermeulen, Louis
AU - Clevers, Hans
AU - Medema, Jan Paul
PY - 2016
Y1 - 2016
N2 - 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
AB - 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
U2 - https://doi.org/10.15252/emmm.201606184
DO - https://doi.org/10.15252/emmm.201606184
M3 - Article
C2 - 27221051
SN - 1757-4676
VL - 8
SP - 745
EP - 760
JO - EMBO molecular medicine
JF - EMBO molecular medicine
IS - 7
ER -