Abstract LB227: Adipokine adipsin promotes breast cancer progression by inducing adipocyte maturation

Abstract Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer-related death among women worldwide. Despite advances in diagnosis and treatment, advanced-stage metastatic breast cancer remains difficult to cure. Adipocytes have long been recognized for their essential roles in both normal and malignant breast tissue biology. Obesity, characterized by the excessive accumulation of mature adipocytes, is a known risk factor for breast cancer progression. Therefore, targeting adipocytes and their interactions with cancer cells will offer novel therapeutic strategies for breast cancer. We established patient-derived tumor xenografts (PDXs) and adipose tissue-derived stem cells (ADSCs) from surgical specimens of breast cancer patients. ADSCs significantly promote cancer stem cell properties, tumor invasion, and metastasis of breast cancer cells. Using Cfd (complement factor D, also known as adipsin) knockout (KO) mice and mammary ADSCs (mADSCs) derived from them, we found that Cfd deficiency in mADSCs markedly reduced their ability to enhance tumorsphere formation by cocultured breast cancer PDX cells. Hepatocyte growth factor (HGF), an adipokine secreted by mADSCs in a CFD-dependent manner, rescued the impaired tumorsphere formation and in vivo tumorigenicity of breast cancer PDX cells induced by Cfd-KO mADSCs. Furthermore, we observed that breast cancer cell migration and invasion were significantly promoted by mature adipocytes—but not by their precursors (i.e., ADSCs)—in an adipsin- and HGF-dependent manner. Adipsin is a secreted serine protease traditionally known for activating the alternative complement pathway and regulating systemic metabolism. It is predominantly secreted by mammary ADSCs, and its expression increases during adipocyte maturation. We found that the absence of adipsin suppressed lipid droplet (LD) formation, a hallmark of adipocyte maturation. Although adipsin is highly expressed in adipocytes, its role in adipogenesis remains poorly understood. In this study, we investigated the role of adipsin in adipocyte maturation using mADSCs isolated from wild-type (WT) and Cfd-KO mice. We found that CFD deficiency significantly reduced LD formation in mature adipocytes. Lentiviral expression of a secretion signal-deficient (SD) or catalytically inactive CFD mutant, as well as the cytosolic (non-secreted) CFD3 splice variant, restored LD formation to WT levels in Cfd-KO adipocytes. These findings suggest that intracellular CFD promotes LD biogenesis in a manner independent of its catalytic activity. Together, our findings reveal a previously unrecognized intracellular function of CFD in regulating lipid droplet biogenesis during adipocyte differentiation. Given that adipocyte maturation strongly promotes breast cancer progression, elucidating the roles of mammary adipocytes and adipokines such as adipsin and HGF will propose novel ways for therapeutic intervention in breast cancer. Citation Format: Yohei Shimono, Behnoush Khaledian, Masahiro Mizuno, Jumpei Yoshida, Kazutsune Yamagata, Takuya Kato, Lisa Thibes, Satoru Ishihara, Fujiko Sueishi, Yuko Kijima, Motoshi Suzuki, Kenji Kawada, Naoya Asai. Adipokine adipsin promotes breast cancer progression by inducing adipocyte maturation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB227.