Adipocyte-specific Zeb1 downregulation remodels the tumor-associated adipose microenvironment to facilitate female breast cancer progression

Lixia Cao, Wei Sun, Xiao Chen, Lei Liu, Shaorong Zhao, Jingjing Liu, Yang Ou, Min Guo, Chunchun Qi, Zhaoxian Li, Jie Shi, Yuxin Liu, Qiuying Shuai, Siyu Zuo, Huayu Hu, Tianwen Yu, Yanjing Wang, Mengdan Feng, Jianying Lv, Hang Wang, Peiqing Sun, Jin Zhang, Longlong Wang, Yi Shi () and Shuang Yang ()
Additional contact information
Lixia Cao: Nankai University
Wei Sun: Nankai University
Xiao Chen: Nankai University
Lei Liu: Tianjin Medical University Cancer Institute & Hospital
Shaorong Zhao: Tianjin Medical University Cancer Institute & Hospital
Jingjing Liu: Tianjin Medical University Cancer Institute & Hospital
Yang Ou: Nankai University
Min Guo: Nankai University
Chunchun Qi: Nankai University
Zhaoxian Li: Nankai University
Jie Shi: Nankai University
Yuxin Liu: Nankai University
Qiuying Shuai: Nankai University
Siyu Zuo: Nankai University
Huayu Hu: Nankai University
Tianwen Yu: Nankai University
Yanjing Wang: Nankai University
Mengdan Feng: Nankai University
Jianying Lv: Nankai University
Hang Wang: Nankai University
Peiqing Sun: Winston
Jin Zhang: Tianjin Medical University Cancer Institute & Hospital
Longlong Wang: Nankai University
Yi Shi: Nankai University
Shuang Yang: Nankai University

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: Abstract Upon penetrating the basement membrane, breast cancer cells directly interact with their surrounding adipose tissue, which forms a unique tumor-associated adipose microenvironment (TAME). However, the underlying mechanism of lipid metabolic remodeling in the TAME remains elusive. Herein, we report a Zeb1-orchestrated bidirectional communication between breast cancer cells and their adjacent cancer-associated adipocytes (CAAs). At the molecular level, breast cancer cells, through the secretion of adrenomedullin (AM), induce downregulation of Zeb1 expression to activate the Atgl/Hsl/Scd-dependent lipolysis in CAAs, resulting in the release of palmitoleic acid (POA) into the TAME. In turn, the increased POA in breast cancer competes with arachidonic acid (ARA) for the phospholipid synthesis, leaving more ARA is utilized for PDG2 production to trigger the malignant progression of breast cancer and AM production. Importantly, disruption of Zeb1-dependent lipolytic activity and/or membrane phospholipid remodeling within the TAME dramatically diminishes the aggressiveness of breast cancer in vitro and in vivo.

Date: 2025
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DOI: 10.1038/s41467-025-61088-3

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