Oncogenic mutations in intestinal adenomas regulate Bim-mediated apoptosis induced by TGF-β.
In the majority of microsatellite-stable colorectal cancers (CRCs), an initiating mutation occurs in the adenomatous polyposis coli (APC) or β-catenin gene, activating the β-catenin/TCF pathway. The progression of resulting adenomas is associated with oncogenic activation of KRas and inactivation of the p53 and TGF-β/Smad functions. Most established CRC cell lines contain mutations in the TGF-β/Smad pathway, but little is known about the function of TGF-β in the early phases of intestinal tumorigenesis. We used mouse and human ex vivo 3D intestinal organoid cultures and in vivo mouse models to study the effect of TGF-β on the Lgr5(+) intestinal stem cells and their progeny in intestinal adenomas. We found that the TGF-β-induced apoptosis in Apc-mutant organoids, including the Lgr5(+) stem cells, was mediated by up-regulation of the BH3-only proapoptotic protein Bcl-2-like protein 11 (Bim). BH3-mimetic compounds recapitulated the effect of Bim not only in the adenomas but also in human CRC organoids that had lost responsiveness to TGF-β-induced apoptosis. However, wild-type intestinal crypts were markedly less sensitive to TGF-β than Apc-mutant adenomas, whereas the KRas oncogene increased resistance to TGF-β via the activation of the Erk1/2 kinase pathway, leading to Bim down-regulation. Our studies identify Bim as a critical mediator of TGF-β-induced apoptosis in intestinal adenomas and show that the common progression mutations modify Bim levels and sensitivity to TGF-β during intestinal adenoma development.
Translational Cancer Biology Program and.
Zoltán
Z
Wiener
Translational Cancer Biology Program and.
Arja M
AM
Band
Translational Cancer Biology Program and.
Pauliina
P
Kallio
Translational Cancer Biology Program and.
Jenny
J
Högström
Translational Cancer Biology Program and.
Ville
V
Hyvönen
Translational Cancer Biology Program and.
Seppo
S
Kaijalainen
Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, FI-00014, Helsinki, Finland;
Olli
O
Ritvos
Department of Surgery, Helsinki University Central Hospital, University of Helsinki, FI-00029, Helsinki, Finland;
Caj
C
Haglund
Department of Surgery, Helsinki University Central Hospital, University of Helsinki, FI-00029, Helsinki, Finland;
Olli
O
Kruuna
Unité Mixte de Recherche 144, Centre National de la Recherche Scientifique, Institut Curie, F-75248 Paris, France; and.
Sylvie
S
Robine
Unité Mixte de Recherche 144, Centre National de la Recherche Scientifique, Institut Curie, F-75248 Paris, France; and.
Daniel
D
Louvard
Lautenberg Center for Immunology, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
Yinon
Y
Ben-Neriah
Translational Cancer Biology Program andWihuri Research Institute, Biomedicum Helsinki, University of Helsinki, FI-00014, Helsinki, Finland; kari.alitalo@helsinki.fi.
Kari
K
Alitalo
D000236:Adenoma / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D015153:Blotting, Western; D002478:Cells, Cultured; D002850:Chromatography, Gel; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D007414:Intestinal Neoplasms / Q000235:genetics*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D046228:Microarray Analysis; D009940:Organoids / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D017931:DNA Primers; C116884:LGR5 protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D016212:Transforming Growth Factor beta
ABT-263; ABT-737; Wnt pathway; colon cancer; crypt culture