Abstract LB078: Adipocytes promote cancer stem cell properties and metastatic progression in breast cancers

Abstract Breast cancer is the most frequently diagnosed cancer and the leading global cause of cancer death in women. Despite advances in the diagnosis and treatment, advanced stage, metastatic breast cancers are difficult to cure. Therapeutic resistance, immune evasion, invasion, and metastasis are at least partly attributed to the behavior of cancer stem cells (CSCs), a sub-population of the cells that retain high tumorigenic capacity and have a higher ability to sustain the tumor formation. We and others have shown that in breast cancers, the self-renewal ability of cancer cells with CSC properties is epigenetically regulated by their expression of microRNAs, such as miR-200c, miR-142 and miR-221. We then have shown that upregulation of S100A10 and downregulation of miR-93 promote distant metastases of breast CSCs. Mammary adipocytes have long been recognized for their essential role both in normal and malignant breast biology. Growth and function of mammary epithelial cells forming a milk-producing ductal system are dependent on the presence of mammary adipocytes; and during subsequent involution and the regression of the milk-producing unit, adipocytes occupy the vacated space. However, molecular mechanisms for the essential requirements of mammary adipocytes as stem cell niche and for the development of normal and malignant mammary tissues remain to be elucidated. We have established the patient derived tumor xenografts (PDXs) and adipose tissue-derived stem cells (ADSCs) from the surgical specimens of breast cancer patients. Adipokine adipsin (complement factor D, CFD) was secreted predominantly from mammary ADSCs (mADSCs) and enhanced the CSC properties of breast cancer PDX cells. Using the Cfd-knockout (KO) mice and mADSCs established from them, we found that Cfd-KO in mADSCs significantly reduced their ability to enhance tumorsphere formation by the breast cancer PDX cells cocultured with mADSCs, which was restored by addition of CFD in the culture medium. Hepatocyte growth factor (HGF) was an adipokine secreted from mADSCs in a CFD-dependent manner. HGF rescued the reduced ability of Cfd-KO mADSCs to promote tumorsphere formation in vitro and tumor formation in vivo by breast cancer PDX cells. Finally, we found that maturation of mammary adipocytes is a strong inducer of tumor progression in breast cancers. Breast cancer cell migration and invasion were significantly induced by mature adipocytes, but not by their precursors (i.e. ADSCs), in adipsin and HGF dependent manners; and tumor growth, invasion and distant metastasis of the mammary cancer cells were significantly suppressed in the Cfd-KO mice. Our results suggest that uncovering the roles of mammary adipocytes and adipokines, such as adipsin and HGF, in CSC-niche interaction and tumor progression will pave the way for novel approaches to suppress breast cancers. Citation Format: Yohei Shimono, Masahiro Mizuno, Jumpei Yoshida, Behnoush Khaledian, Hideaki Goto, Fujiko Sueishi, Takanori Hayashi, Yohei Funakoshi, Hironobu Minami, Kenji Kawada, Yuko Kijima, Motoshi Suzuki, Naoya Asai. Adipocytes promote cancer stem cell properties and metastatic progression in breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB078.