AKT-dependent NOTCH3 activation drives tumor progression in a model of mesenchymal colorectal cancer.
Animals
Colorectal Neoplasms
/ metabolism
Disease Models, Animal
Disease Progression
Gene Expression Regulation, Neoplastic
Humans
Mice
Mice, Inbred C57BL
Neoplasm Transplantation
Proto-Oncogene Proteins c-akt
/ metabolism
Receptor, Notch3
/ metabolism
Signal Transduction
Transcriptome
Up-Regulation
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
05 10 2020
05 10 2020
Historique:
received:
14
08
2019
revised:
26
03
2020
accepted:
05
06
2020
entrez:
5
8
2020
pubmed:
5
8
2020
medline:
11
3
2021
Statut:
ppublish
Résumé
Recently, a transcriptome-based consensus molecular subtype (CMS) classification of colorectal cancer (CRC) has been established, which may ultimately help to individualize CRC therapy. However, the lack of animal models that faithfully recapitulate the different molecular subtypes impedes adequate preclinical testing of stratified therapeutic concepts. Here, we demonstrate that constitutive AKT activation in intestinal epithelial cells markedly enhances tumor invasion and metastasis in Trp53ΔIEC mice (Trp53ΔIECAktE17K) upon challenge with the carcinogen azoxymethane. Gene-expression profiling indicates that Trp53ΔIECAktE17K tumors resemble the human mesenchymal colorectal cancer subtype (CMS4), which is characterized by the poorest survival rate among the four CMSs. Trp53ΔIECAktE17K tumor cells are characterized by Notch3 up-regulation, and treatment of Trp53ΔIECAktE17K mice with a NOTCH3-inhibiting antibody reduces invasion and metastasis. In CRC patients, NOTCH3 expression correlates positively with tumor grading and the presence of lymph node as well as distant metastases and is specifically up-regulated in CMS4 tumors. Therefore, we suggest NOTCH3 as a putative target for advanced CMS4 CRC patients.
Identifiants
pubmed: 32749453
pii: 151998
doi: 10.1084/jem.20191515
pmc: PMC7537393
pii:
doi:
Substances chimiques
Notch3 protein, mouse
0
Receptor, Notch3
0
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2020 Varga et al.
Déclaration de conflit d'intérêts
Disclosures: T. Oellerich reported grants from Merck KGaA, grants from Gilead, personal fees from Merck KGaA, and personal fees from Gilead outside the submitted work. C. Siebel reported personal fees from Genentech during the conduct of the study, and personal fees from Genentech outside the submitted work. In addition, C. Siebel had a patent to Methods of treating cancer using Notch1 and Notch3 antagonists issued. No other disclosures were reported.
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