Adipocyte-specific Zeb1 confers breast cancer progression by triggering the tumor-associated adipose microenvironment remodeling

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 involved in the regulation of lipid metabolic remodeling in the TAME remains elusive. Herein, we identified 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-depedent lipolysis in CAAs, which subsequently results in the release of palmitoleic acid (POA) into the TAME. In turn, accumulated POA triggers the malignant growth and metastasis of breast cancer cells and their production of AM via an ARA-PDG2-mediated membrane phospholipid replacement mechanism. Importantly, disruption of Zeb1-dependent lipolytic activity and/or membrane phospholipid remodeling within the TAME, severely diminishes the aggressiveness of breast cancer in vitro and in vivo.