RRC ID 79484
Author Song Y, Na H, Lee SE, Kim YM, Moon J, Nam TW, Ji Y, Jin Y, Park JH, Cho SC, Lee J, Hwang D, Ha SJ, Park HW, Kim JB, Lee HW.
Title Dysfunctional adipocytes promote tumor progression through YAP/TAZ-dependent cancer-associated adipocyte transformation.
Journal Nat Commun
Abstract 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.
Volume 15(1)
Pages 4052
Published 2024-5-14
DOI 10.1038/s41467-024-48179-3
PII 10.1038/s41467-024-48179-3
PMID 38744820
PMC PMC11094189
MeSH Adaptor Proteins, Signal Transducing* / genetics Adaptor Proteins, Signal Transducing* / metabolism Adipocytes* / metabolism Adipocytes* / pathology Animals Cell Cycle Proteins / genetics Cell Cycle Proteins / metabolism Cell Transformation, Neoplastic / genetics Cell Transformation, Neoplastic / metabolism Cell Transformation, Neoplastic / pathology Diet, High-Fat* / adverse effects Disease Progression Humans Lipodystrophy / genetics Lipodystrophy / metabolism Lipodystrophy / pathology Male Mice Mice, Inbred C57BL Mice, Knockout* Neoplasms / genetics Neoplasms / metabolism Neoplasms / pathology Obesity / metabolism Obesity / pathology Signal Transduction Trans-Activators / genetics Trans-Activators / metabolism Transcription Factors / genetics Transcription Factors / metabolism Transcriptional Coactivator with PDZ-Binding Motif Proteins Tumor Microenvironment* Verteporfin / pharmacology YAP-Signaling Proteins* / metabolism
Mice RBRC02759