Altered adipose-derived mesenchymal stem/stromal cells induced by obesity in the breast cancer microenvironment

Abstract It is well documented that obesity, characterized by an increased body mass index (BMI≥30), is an important risk factor for the development of aggressive breast cancer (BC), which is associated with a reduced overall survival rate and decreased treatment response. The tumor microenvironment (TME), a cellular network majorly constructed by adipocytes, adipose-derived mesenchymal stem/stromal cells (bASCs) and immune cells, impacts progression of breast cancer and treatment response of patients. This study aims to examine how obesity influences the functional characteristics of bASCs in comparison to lean bASCs in the TME. To address this issue, various molecular, biological and cellular methods are applied including transcriptomic profiling and functional assays to characterize at first the features of bASCs in the TME (adjacent to tumor; -aT/distant to tumor; -dT) in obese (ob-) and lean (ln-) bASCs (n=5, for each group) patients with breast cancer. Second, based on the transcriptomic data, we investigated the interaction of bASCs with triple negative as well as triple positive BC cell lines in 3D-spheroids and in standard 2D-cell culture conditions.Indicated by the gene signature the TME shifts bASCs towards a cancer supporting phenotype with a significant deregulated protein expression, cytokine/chemokine secretion, and reduced differentiation capacity. These changes affect critically the cell-cell interaction of BC cells with bASCs. bASCs isolated adjacent to the tumor increase the malignancy of BCs by stimulating the proliferation, migration, invasion and chemoresistance of these cells significantly. These observed effects are further enhanced by ob-aT bASCs. In conclusion, this study identifies over 900 genes deregulated in bASCs adjacent to breast cancer. Many of these genes are associated with pathways known for the development of malignant cells. Moreover, it clarifies differences in obese versus lean bASCs and their impacts on progression of breast cancer cells. Citation Format: Andreas Ritter, Susanne Roth, Alexandra Friemel, Nina-Naomi Kreis, Frank Louwen, Christine Solbach, Juping Yuan. Altered adipose-derived mesenchymal stem/stromal cells induced by obesity in the breast cancer microenvironment [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-11-03.