Abstract 293: Distinctive roles of mammary adipomes in breast cancer progression: Insights from functional analysis and differential gene expression

Abstract

Abstract Breast Cancer (BC) is a heterogeneous disease that impacts treatment response. This is due in part to the tumor microenvironment (TME), which contributes significantly to BC pathogenesis, including metastasis. Women with higher breast density and reduced breast fat face an increased BC risk across multiple tumor subtypes. This is exemplified by the correlation between increased tumor progression, the appearance of fibrosis and the loss of mature adipocytes. While the role of adipokines in this process has been studied extensively, the contribution of adipocyte-derived extracellular vesicles (EV) or "adipomes" in tumorigenesis and metastasis remains poorly understood. To address this question, we developed a novel technique for isolating intact adipomes from normal mammary fat (MF) obtained from wild-type C57BL/6 mice as well as from tumor-associated MF (TAMF) obtained from mice inoculated orthotopically with EO771 mammary tumor cells. Adipome isolation involved high-speed centrifugation to separate macro- and micro-vesicles, purification using the ExoQuick EV isolation system, and immunomagnetic capture of adipomes. Characterization of adipomes by transmission electron microscopy revealed two adipome populations, large L-adipomes of ~350 nm, and small S-adipomes of ~40 nm. Notably, the quantity of L-adipomes in tumor-associated mammary fat (TAMF) was 10-fold greater than the amount of L-adipomes in the MF of non-tumor-bearing mice. To identify possible functional roles of L-adipomes in the pathogenesis of BC, lipidomic profiling was undertaken. L-Adipomes from TAMF showed significantly altered lipid species in comparison to MF-derived L-adipomes. Adipomes were further characterized by treating EO771 cells for 72 hr with TAMF- or MF-derived adipomes at a cell to adipome ratio of 1:10, followed by RNAseq analysis. Differentially upregulated genes in TAMF-derived L-adipomes included Esr1, Erbb2, Tgfb1, Bcl2, MMP2, and Notch associated with fibrosis, EMT, angiogenesis and invasion and downregulation of genes linked to tumor suppression, apoptosis, and mitochondrial metabolism. Overall, our study illustrates the importance of tumor-associated adipomes in regulating gene expression in tumor cells, which emphasizes the specificity of adipome content relating to the cell-of-origin and the host's pathologic and metabolic state and in modulating signaling pathways involved in BC progression. Citation Format: Hariprasad Thangavel, Kezia Lizardo, Robert I. Glazer, Jyothi F. Nagajyothi. Distinctive roles of mammary adipomes in breast cancer progression: Insights from functional analysis and differential gene expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 293.