title: The transcription factor GATA6 enables self-renewal of colon adenoma stem cells by repressing BMP gene expression.
abstract: Aberrant activation of WNT signalling and loss of BMP signals represent the two main alterations leading to the initiation of colorectal cancer (CRC). Here we screen for genes required for maintaining the tumour stem cell phenotype and identify the zinc-finger transcription factor GATA6 as a key regulator of the WNT and BMP pathways in CRC. GATA6 directly drives the expression of LGR5 in adenoma stem cells whereas it restricts BMP signalling to differentiated tumour cells. Genetic deletion of Gata6 from mouse colon adenomas increases the levels of BMP factors, which signal to block self-renewal of tumour stem cells. In human tumours, GATA6 competes with β-catenin/TCF4 for binding to a distal regulatory region of the BMP4 locus that has been linked to increased susceptibility to development of CRC. Hence, GATA6 creates an environment permissive for CRC initiation by lowering the threshold of BMP signalling required for tumour stem cell expansion.
authors: Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain.
authors: Gavin
authors: G
authors: Whissell
authors: 1] Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain [2].
authors: Elisa
authors: E
authors: Montagni
authors: 1] Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain [2].
authors: Paola
authors: P
authors: Martinelli
authors: Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain.
authors: Xavier
authors: X
authors: Hernando-Momblona
authors: Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain.
authors: Marta
authors: M
authors: Sevillano
authors: Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain.
authors: Peter
authors: P
authors: Jung
authors: Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain.
authors: Carme
authors: C
authors: Cortina
authors: Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain.
authors: Alexandre
authors: A
authors: Calon
authors: 1] Department of Gastroenterology, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Catalonia, Spain [2] Department of Gastroenterology, Hospital del Mar-IMIM (Hospital del Mar Medical Research Centre), Pompeu Fabra University, 08003 Barcelona, Catalonia, Spain.
authors: Anna
authors: A
authors: Abuli
authors: Department of Gastroenterology, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Catalonia, Spain.
authors: Antoni
authors: A
authors: Castells
authors: Department of Gastroenterology, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Catalonia, Spain.
authors: Sergi
authors: S
authors: Castellvi-Bel
authors: Centre de Regulació Genòmica (CRG), Universitat Pompeu Fabra (UPF), E-08003 Barcelona, Spain.
authors: Ana Silvina
authors: AS
authors: Nacht
authors: Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain.
authors: Elena
authors: E
authors: Sancho
authors: Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain.
authors: Camille
authors: C
authors: Stephan-Otto Attolini
authors: Centre de Regulació Genòmica (CRG), Universitat Pompeu Fabra (UPF), E-08003 Barcelona, Spain.
authors: Guillermo P
authors: GP
authors: Vicent
authors: 1] Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain [2] Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors: Francisco X
authors: FX
authors: Real
authors: 1] Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain [2] Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain.
authors: Eduard
authors: E
authors: Batlle
mesh_terms: D000236:Adenoma / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D052004:Bone Morphogenetic Protein Receptors / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000503:physiopathology*; D005260:Female; D005455:Fluorescent Antibody Technique; D050993:GATA6 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D050993:GATA6 Transcription Factor; C554430:LDN 193189; D011720:Pyrazoles; D011743:Pyrimidines; D051153:Wnt Proteins; D052004:Bone Morphogenetic Protein Receptors