Abstract 3589: Adipose stem cell-derived interferon gamma alters breast epithelial stem cell hierarchy

Abstract

Abstract Autologous adipose stem cell transplantation is increasingly being used for soft tissue reconstruction, particularly after mastectomy. However, a recent study demonstrated recurrence of invasive ductal carcinoma in the breast within four months of autologous fat grafting. Previous studies have documented how cancer cells commandeer adipose stem cells (ASC) to support their survival by altering extracellular matrix composition and stiffness. This study focused on delineating the effects of ASCs on the self-renewal capacity of breast epithelial cells. The immortalized breast epithelial cell line MCF-10A, MCF-10A overexpressing Slug, and MCF-10A overexpressing SRC were examined using a mammosphere assay and flow cytometry for the effects of ASCs on their self-renewal and stem-luminal progenitor-differentiated cell surface marker profile. MCF-10A-Slug cells provided a unique model system to study breast epithelial cell dedifferentiation as Slug functions downstream of the breast cancer susceptibility gene BRCA1 and is a major suppressor of progenitor cell lineage commitment and differentiation. Interestingly, results with these established cell lines were reproduced in primary breast epithelial cells isolated from a high-risk patient. We show that secreted factors from ASCs promote self-renewal of all cell types examined. ASC co-culture or treatment with ASC conditioned media (CM) altered the number of CD49fhigh/EpCAMlow stem-like and CD49fmedium/EpCAMmedium luminal progenitor cells in 2D culture and mammosphere assays. ASCs secrete Interferon gamma (IFNγ), CD40 ligand, IL-23 and SERPINE1. Among these factors, only IFNγ treatment altered stem cell hierarchy; while MCF-10A-Slug cells displayed only luminal progenitor phenotype, cells treated with IFNγ contained a distinct stem-like cell population. These results suggest that paracrine activity of adipose stem cell-derived factors can either enhance dedifferentiation and promote proliferation of dormant tumor cells or predispose normal cells to transformation by blocking differentiation. Financial support: Susan G. Komen For the Cure SAC110025 and Zeta Tau Sorority (HN) Citation Format: Manjushree Anjanappa, Riesa M. Burnett, Stephanie Merfeld-Clauss, William A. Wooden, Keith L. March, Sunil Tholpady, Harikrishna Nakshatri. Adipose stem cell-derived interferon gamma alters breast epithelial stem cell hierarchy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3589. doi:10.1158/1538-7445.AM2014-3589