Abstract B51: Modeling the intrinsic and extrinsic influences on breast cancer phenotypic heterogeneity using mouse models and three-dimensional bioprinting
Authors: Langer Ellen M. , Wang Xiaoyan , Liang Juan , Allen-Petersen Brittany L. , Kendsersky Nicholas D. , Risom Tyler , Pelz Carl , Sears Rosalie C. 
Published: May 2016

Breast cancer cells exhibit intertumoral and intratumoral heterogeneity due to both tumor cell intrinsic and extrinsic influence. We have been modeling phenotypic heterogeneity in breast cancer using multiple model systems to interrogate the causes of this heterogeneity as well as its effects on therapeutic resistance. Toward this end, we generated a novel, genetically-engineered mouse model of triple negative breast cancer driven by loss of PTEN in combination with low-level deregulated c-Myc expression. Expression of deregulated Myc significantly accelerates tumorigenesis in this model. Histologic and global gene expression analyses reveal that this model generates predominately two phenotypic groups within triple negative breast cancer. One group is composed of fibrotic tumors that have increased ECM deposition as well as increased alpha-Smooth Muscle Actin (SMA) and Fibroblast Associated Protein (FAP) expression in the stroma. These tumors express a Claudin-low molecular signature and have high p-SMAD3 expression. The second group is composed of adenocarcinomas that have less stromal involvement and decreased ECM deposition. In preliminary studies, the more fibrotic tumors exhibit increased resistance to targeted therapeutics. To better understand if this resistance is due to intrinsic or extrinsic influence, we are generating primary cultures of both the tumor and stromal cells from these mice. Through additional in vitro and in vivo studies, we will interrogate the mechanisms of therapeutic resistance. To build upon this approach, we are also utilizing three-dimensional bioprinting to model the heterogeneity of tumor/stroma interactions with human cell lines or primary cultures. For this model, we surround breast cancer cells with stromal cells of the tumor microenvironment, including fibroblasts and endothelial cells. As the structures mature over the course of 1-3 weeks, the cells within these tissues self-organize and respond to extrinsic signals. In this system, we can assess the contribution of distinct cell types to the overall histology of the tissues as well as interrogate the mechanisms driving specific phenotypes by manipulating either the tumor or stromal cells prior to printing. Together, analysis of both the mouse models and bioprinted human tissues will help reveal nodes of crosstalk between breast tumor cells and cells within the microenvironment that affect baseline phenotypic heterogeneity and/or therapeutic efficacy.

Citation Format: Ellen M. Langer, Xiaoyan Wang, Juan Liang, Brittany L. Allen-Petersen, Nicholas D. Kendsersky, Tyler Risom, Carl Pelz, Rosalie C. Sears. Modeling the intrinsic and extrinsic influences on breast cancer phenotypic heterogeneity using mouse models and three-dimensional bioprinting. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B51.