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Cellular and Molecular Biology

Breast cancer cell-derived adrenomedullin confers cancer-associated adipose remodeling through the cAMP/Creb1/Zeb1 axis

British Journal of Cancer (2025)Cite this article

Subjects

Abstract

Background

Breast cancer cells that break through the basement membrane interact directly with neighboring adipocytes. Therefore, adipocytes adjacent to the invasive front of tumour undergo lipolysis and transform into cancer-associated adipocytes (CAAs), which is vital for the malignant progression of breast cancer. However, tumor-derived factors that trigger this process are still to be determined.

Methods

Transcriptome sequencing was used to identify the downstream transcription factor of adrenomedullin (AM). Tet-On system was used to construct the 3T3-L1 cell line with inducible overexpression of Zeb1. Adipocyte-specific knock-in Zeb1 transgenic mice (Zeb1adiTG) were used to construct an allograft tumor model.

Results

Breast cancer cell-derived AM downregulated the transcriptional expression of Zeb1 by triggering the cAMP/PKA/Creb1 pathway, thereby exerting lipolytic effects in CAAs. On the contrary, adipose tissue-specific upregulation of Zeb1 significantly attenuated AM-induced lipolytic phenotypes. Of note, we used the Zeb1adiTG mice to construct allograft tumor models. The results confirmed that breast cancer cell-derived AM conferred tumorigenicity in vivo, which effect was predominantly dependent on the aberrant expression of adipocyte-specific Zeb1.

Conclusions

These findings collectively suggested that breast cancer cell-derived AM promotes lipid metabolic reprogramming through a Zeb1-dependent manner in CAAs, which displays significant clinical implications and may provide promising therapeutic approaches for targeting the breast cancer-associated adipose microenvironment.

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Fig. 1: Breast cancer cell-derived AM confers the lipolysis of adipocytes through a paracrine action.
Fig. 2: AM-mediated TAME remodelling leads to the malignant progression of breast cancer in vivo.
Fig. 3: AM regulates the lipid metabolic remodelling in a Zeb1-dependent action in adipocytes.
Fig. 4: AM acts on adipocytes by activating the cAMP/PKA/Creb1 pathway to trigger the downregulation of Zeb1 expression.
Fig. 5: Adipose tissue-specific upregulation of Zeb1 significantly attenuates AM-induced lipolytic phenotypes.
Fig. 6: Adipocyte-specific upregulation of Zeb1 expression attenuates the AM-induced malignant phenotypes of breast cancer.
Fig. 7: The expression of AM and Zeb1 is correlated in human breast cancer specimens.

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Data availability

The RNA-seq data generated in this study have been deposited in NCBI_SRA database under accession code PRJNA1297415 (https://www.ncbi.nlm.nih.gov/sra/?term=PRJNA1297415). All the other data supporting the findings of this study are available within the article and its Supplementary Information files.

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Acknowledgements

This work was supported by grants from the International Science and Technology Cooperation Project of China (No. 2022YFE0133300) and the National Natural Science Foundation of China (No. 82472870; No. 82172801).

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Author notes

  1. These authors contributed equally: Xiao Chen, Lixia Cao.

Authors and Affiliations

  1. Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin, China

    Xiao Chen, Lixia Cao, Mengdan Feng, Qiuying Shuai, Min Guo, Zhaoxian Li, Chunchun Qi, Jie Shi, Yuxin Liu, Siyu Zuo, Tianwen Yu, Huayu Hu, Yanjing Wang, Yao Xue, Yi Shi, Hang Wang & Shuang Yang

  2. Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    Peiqing Sun

  3. The Third Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

    Lei Liu

  4. Tianjin’s Clinical Research Center for Cancer; Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China

    Lei Liu

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  1. Xiao Chen
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Contributions

XC and LC contributed to conceptualisation, methodology, data curation, and writing—original draft. MF and QS performed visualisation, methodology, investigation, and formal analysis. MG, ZL, CQ, JS, and SZ carried out methodology and formal analysis. YL, TY, HH, YW, and YX contributed to methodology and conceptualisation. PS and YS conducted visualisation and validation. HW provided resources and funding acquisition. LL supervised the study, provided resources, secured funding, and participated in data curation, conceptualisation, and writing—review & editing. SY supervised the study, provided resources, project administration, and funding acquisition, and contributed to visualisation, methodology, formal analysis, data curation, conceptualisation, and writing—review & editing. All authors read and approved the final version of the manuscript.

Corresponding authors

Correspondence to Hang Wang, Lei Liu or Shuang Yang.

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The study was conformed to the principles of the Declaration of Helsinki, and all of the experimental procedures involving animals were performed in accordance with a protocol that was approved by the Ethics Committee for Animal Use at the Medical College of Nankai University (2022-SYDWLL-000096).

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Chen, X., Cao, L., Feng, M. et al. Breast cancer cell-derived adrenomedullin confers cancer-associated adipose remodeling through the cAMP/Creb1/Zeb1 axis. Br J Cancer (2025). https://doi.org/10.1038/s41416-025-03219-7

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