Titre
BCL-XL is crucial for progression through the adenoma-to-carcinoma sequence of colorectal cancer.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Ramesh, P.
Auteure/Auteur
Lannagan, TRM
Auteure/Auteur
Jackstadt, R.
Auteure/Auteur
Atencia Taboada, L.
Auteure/Auteur
Lansu, N.
Auteure/Auteur
Wirapati, P.
Auteure/Auteur
van Hooff, S.R.
Auteure/Auteur
Dekker, D.
Auteure/Auteur
Pritchard, J.
Auteure/Auteur
Kirov, A.B.
Auteure/Auteur
van Neerven, S.M.
Auteure/Auteur
Tejpar, S.
Auteure/Auteur
Kops, GJPL
Auteure/Auteur
Sansom, O.J.
Auteure/Auteur
Medema, J.P.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
1476-5403
Statut éditorial
Publié
Date de publication
2021-12
Volume
28
Numéro
12
Première page
3282
Dernière page/numéro d’article
3296
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Résumé
Evasion of apoptosis is a hallmark of cancer, which is frequently mediated by upregulation of the antiapoptotic BCL-2 family proteins. In colorectal cancer (CRC), previous work has highlighted differential antiapoptotic protein dependencies determined by the stage of the disease. While intestinal stem cells (ISCs) require BCL-2 for adenoma outgrowth and survival during transformation, ISC-specific MCL1 deletion results in disturbed intestinal homeostasis, eventually contributing to tumorigenesis. Colon cancer stem cells (CSCs), however, no longer require BCL-2 and depend mainly on BCL-XL for their survival. We therefore hypothesized that a shift in antiapoptotic protein reliance occurs in ISCs as the disease progresses from normal to adenoma to carcinoma. By targeting antiapoptotic proteins with specific BH3 mimetics in organoid models of CRC progression, we found that BCL-2 is essential only during ISC transformation while MCL1 inhibition did not affect adenoma outgrowth. BCL-XL, on the other hand, was crucial for stem cell survival throughout the adenoma-to-carcinoma sequence. Furthermore, we identified that the limited window of BCL-2 reliance is a result of its downregulation by miR-17-5p, a microRNA that is upregulated upon APC-mutation driven transformation. Here we show that BCL-XL inhibition effectively impairs adenoma outgrowth in vivo and enhances the efficacy of chemotherapy. In line with this dependency, expression of BCL-XL, but not BCL-2 or MCL1, directly correlated to the outcome of chemotherapy-treated CRC patients. Our results provide insights to enable the rational use of BH3 mimetics in CRC management, particularly underlining the therapeutic potential of BCL-XL targeting mimetics in both early and late-stage disease.
PID Serval
serval:BIB_59DEDA1B732A
PMID
Open Access
Oui
Date de création
2021-06-28T10:25:28.269Z
Date de création dans IRIS
2025-05-20T17:02:38Z
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Nom
34117376_BIB_59DEDA1B732A.pdf
Version du manuscrit
published
Licence
https://creativecommons.org/licenses/by/4.0
Taille
2.37 MB
Format
Adobe PDF
PID Serval
serval:BIB_59DEDA1B732A.P001
URN
urn:nbn:ch:serval-BIB_59DEDA1B732A6
Somme de contrôle
(MD5):13dd09aba85ded8ab775152362e02dfb