Dysfunctional adipocytes promote tumor progression through YAP/TAZ-dependent cancer-associated adipocyte transformation.
Animals
YAP-Signaling Proteins
/ metabolism
Adipocytes
/ metabolism
Adaptor Proteins, Signal Transducing
/ metabolism
Mice
Tumor Microenvironment
Mice, Knockout
Diet, High-Fat
/ adverse effects
Transcription Factors
/ metabolism
Obesity
/ metabolism
Humans
Verteporfin
/ pharmacology
Signal Transduction
Transcriptional Coactivator with PDZ-Binding Motif Proteins
Disease Progression
Male
Cell Transformation, Neoplastic
/ metabolism
Neoplasms
/ metabolism
Cell Cycle Proteins
/ metabolism
Lipodystrophy
/ metabolism
Mice, Inbred C57BL
Trans-Activators
/ metabolism
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
14 May 2024
14 May 2024
Historique:
received:
19
06
2023
accepted:
23
04
2024
medline:
15
5
2024
pubmed:
15
5
2024
entrez:
14
5
2024
Statut:
epublish
Résumé
Obesity has emerged as a prominent risk factor for the development of malignant tumors. However, the existing literature on the role of adipocytes in the tumor microenvironment (TME) to elucidate the correlation between obesity and cancer remains insufficient. Here, we aim to investigate the formation of cancer-associated adipocytes (CAAs) and their contribution to tumor growth using mouse models harboring dysfunctional adipocytes. Specifically, we employ adipocyte-specific BECN1 KO (BaKO) mice, which exhibit lipodystrophy due to dysfunctional adipocytes. Our results reveal the activation of YAP/TAZ signaling in both CAAs and BECN1-deficient adipocytes, inducing adipocyte dedifferentiation and formation of a malignant TME. The additional deletion of YAP/TAZ from BaKO mice significantly restores the lipodystrophy and inflammatory phenotypes, leading to tumor regression. Furthermore, mice fed a high-fat diet (HFD) exhibit decreased BECN1 and increased YAP/TAZ expression in their adipose tissues. Treatment with the YAP/TAZ inhibitor, verteporfin, suppresses tumor progression in BaKO and HFD-fed mice, highlighting its efficacy against mice with metabolic dysregulation. Overall, our findings provide insights into the key mediators of CAA and their significance in developing a TME, thereby suggesting a viable approach targeting adipocyte homeostasis to suppress cancer growth.
Identifiants
pubmed: 38744820
doi: 10.1038/s41467-024-48179-3
pii: 10.1038/s41467-024-48179-3
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
4052Informations de copyright
© 2024. The Author(s).
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