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TGFß signaling directs serrated adenomas to the mesenchymal colorectal cancer subtype.
Fessler, Evelyn; Drost, Jarno; van Hooff, Sander R; Linnekamp, Janneke F; Wang, Xin; Jansen, Marnix; De Sousa E Melo, Felipe; Prasetyanti, Pramudita R; IJspeert, Joep Eg; Franitza, Marek; Nürnberg, Peter; van Noesel, Carel Jm; Dekker, Evelien; Vermeulen, Louis; Clevers, Hans; Medema, Jan Paul.
Afiliación
  • Fessler E; 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.
  • Drost J; Cancer Genomics Center, Amsterdam, The Netherlands Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, Utrecht, The Netherlands.
  • van Hooff SR; 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.
  • Linnekamp JF; 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.
  • Wang X; Department of Biomedical Sciences, City University of Hong Kong, Kowloon Tong, Hong Kong.
  • Jansen M; Department of Pathology, AMC, University of Amsterdam, Amsterdam, The Netherlands.
  • De Sousa E Melo F; 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.
  • Prasetyanti PR; 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.
  • IJspeert JE; Department of Gastroenterology, AMC, University of Amsterdam, Amsterdam, The Netherlands.
  • Franitza M; 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.
  • Nürnberg P; 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.
  • van Noesel CJ; Department of Pathology, AMC, University of Amsterdam, Amsterdam, The Netherlands.
  • Dekker E; Department of Gastroenterology, AMC, University of Amsterdam, Amsterdam, The Netherlands.
  • Vermeulen L; Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands.
  • Clevers H; Cancer Genomics Center, Amsterdam, The Netherlands Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, Utrecht, The Netherlands.
  • Medema JP; 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.
EMBO Mol Med ; 8(7): 745-60, 2016 07.
Article en En | MEDLINE | ID: mdl-27221051
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 TGFß 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 TGFß is death by apoptosis. By contrast, induction of a mesenchymal phenotype upon TGFß 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 TGFß signaling is already active in SSA precursor lesions and that TGFß is a critical cue for directing SSAs to the mesenchymal, poor-prognosis CMS4 of CRC.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Neoplasias Colorrectales / Transducción de Señal / Adenoma / Factor de Crecimiento Transformador beta / Carcinogénesis Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: EMBO Mol Med Asunto de la revista: BIOLOGIA MOLECULAR Año: 2016 Tipo del documento: Article País de afiliación: Países Bajos

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Neoplasias Colorrectales / Transducción de Señal / Adenoma / Factor de Crecimiento Transformador beta / Carcinogénesis Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: EMBO Mol Med Asunto de la revista: BIOLOGIA MOLECULAR Año: 2016 Tipo del documento: Article País de afiliación: Países Bajos