Exosomes from the tumour-adipocyte interplay stimulate beige/brown differentiation and reprogram metabolism in stromal adipocytes to promote tumour progression

Abstract

Background Emerging evidence supports the pivotal roles of adipocytes in breast cancer progression. Tumour induced beige/brown adipose tissue differentiation contributes to the hypermetabolic state of the breast cancer. However, the mediators and mechanisms remain unclear. Methods Survival probabilities were estimated using the Kaplan–Meier method based on immunohistochemistry results. Biochemical studies were performed to characterize the novel interrelation between breast cancer cells and adipocytes. Results We show that tumour-surrounding adipocytes exhibit an altered phenotype in terms of upregulated beige/brown characteristics and increased catabolism associated with an activated state characterized by the release of metabolites, including free fatty acids, pyruvate, lactate and ketone bodies. Likewise, tumour cells cocultivated with mature adipocytes exhibit metabolic adaptation and an aggressive phenotype in vitro and in vivo. Mechanistically, we show that tumour cells induce beige/brown differentiation and remodel metabolism in resident adipocytes by exosomes from the co-culture system that carry high levels of miRNA-144 and miRNA-126. miRNA-144 promotes beige/brown adipocyte characteristics by downregulating the MAP3K8/ERK1/2/PPARγ axis, and exosomal miRNA-126 remodels metabolism by disrupting IRS/Glut-4 signalling, activating the AMPK/autophagy pathway and stabilizing HIF1α expression in imminent adipocytes. In vivo inhibition of miRNA-144 or miRNA-126 decreases adipocyte–induced tumour growth. Conclusions These results demonstrate that by inducing beige/brown differentiation and enhancing catabolism in recipient adipocytes, exosomal miRNA-144 and miRNA-126 from the tumour-adipocyte interaction reprogram systemic energy metabolism to facilitate tumour progression.

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Cited by papers we hold 10

• The pleiotropic roles of adipocyte secretome in remodeling breast cancer · 2022
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• The emerging roles and mechanisms of exosomal non-coding RNAs in the mutual regulation between adipose tissue and other related tissues in obesity and metabolic diseases · 2022
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• Dietary regulation in health and disease · 2022
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• The Metabolic Mechanisms of Breast Cancer Metastasis · 2021
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• Aspects of the Tumor Microenvironment Involved in Immune Resistance and Drug Resistance · 2021
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• Tumor-Associated Macrophages and Their Functional Transformation in the Hypoxic Tumor Microenvironment · 2021
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• Exosome-mediated metabolic reprogramming: the emerging role in tumor microenvironment remodeling and its influence on cancer progression · 2020
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• Cancer-associated adipocytes: emerging supporters in breast cancer · 2020
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• Cancer-associated adipocytes: key players in breast cancer progression · 2019
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• Reprogramming of fatty acid metabolism in cancer · 2019
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