title: TGFβ signaling directs serrated adenomas to the mesenchymal colorectal cancer subtype.
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.
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands Cancer Genomics Center, Amsterdam, The Netherlands.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Fessler
authors.affiliation: Cancer Genomics Center, Amsterdam, The Netherlands Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, Utrecht, The Netherlands.
authors.forename: Jarno
authors.initials: J
authors.lastname: Drost
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands Cancer Genomics Center, Amsterdam, The Netherlands.
authors.forename: Sander R
authors.initials: SR
authors.lastname: van Hooff
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands Cancer Genomics Center, Amsterdam, The Netherlands.
authors.forename: Janneke F
authors.initials: JF
authors.lastname: Linnekamp
authors.affiliation: Department of Biomedical Sciences, City University of Hong Kong, Kowloon Tong, Hong Kong.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pathology, AMC, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Marnix
authors.initials: M
authors.lastname: Jansen
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands Cancer Genomics Center, Amsterdam, The Netherlands.
authors.forename: Felipe
authors.initials: F
authors.lastname: De Sousa E Melo
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands Cancer Genomics Center, Amsterdam, The Netherlands.
authors.forename: Pramudita R
authors.initials: PR
authors.lastname: Prasetyanti
authors.affiliation: Department of Gastroenterology, AMC, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Joep Eg
authors.initials: JE
authors.lastname: IJspeert
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Marek
authors.initials: M
authors.lastname: Franitza
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Department of Pathology, AMC, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Carel Jm
authors.initials: CJ
authors.lastname: van Noesel
authors.affiliation: Department of Gastroenterology, AMC, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Evelien
authors.initials: E
authors.lastname: Dekker
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Louis
authors.initials: L
authors.lastname: Vermeulen
authors.affiliation: Cancer Genomics Center, Amsterdam, The Netherlands Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, Utrecht, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands Cancer Genomics Center, Amsterdam, The Netherlands j.p.medema@amc.nl.
authors.forename: Jan Paul
authors.identifier: 0000-0003-3045-2924
authors.initials: JP
authors.lastname: Medema
mesh_terms: D000236:Adenoma / Q000473:pathology*; D063646:Carcinogenesis; D015179:Colorectal Neoplasms / Q000473:pathology*; D006801:Humans; D009940:Organoids; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D016212:Transforming Growth Factor beta
keywords: cancer subtypes; colorectal cancer; epithelial–mesenchymal transition; sessile serrated adenoma; transforming growth factor beta (TGFβ)