Abstract B17: A microscale 3-D in vitro model of the breast cancer progression from DCIS to IDC: Deciphering the role of the stromal fibroblasts

Abstract

Abstract Breast cancer progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) is a critical step in breast cancer. This invasive transition of DCIS is defined by stromal invasion and is a life-threatening step accompanied by a dramatic drop in prognosis. In addition, the invasive transition of DCIS is largely driven by stromal alteration; thus it is critical to understand how DCIS alters the surrounding microenvironment, thus causing the cancer cells to become invasive. This study investigates the role of stromal fibroblasts in the vicinity of DCIS during the invasive transition using an innovative multidisciplinary approach that combines 3D cancer biology, microfluidics, and high-resolution imaging. We recently developed an efficient 3D microfluidic system that supports the transition from DCIS to IDC. The in vitro system employs microchannels with two inputs and one output enabling MCF10-DCIS.com cells (MCF-DCIS) and human mammary fibroblasts (HMF) to be loaded in two adjacent (side-by-side) compartments. This platform allows investigations of effects of spatial organization on the transition by independently analyzing their morphology and the modifications to the surrounding collagen architecture. Importantly, the compartmentalized platform enables monitoring of both MCF-DCIS and HMF independently including quantitative measures of the collagen architecture associated with each cell type. We observed that the HMF near MCF-DCIS became more protrusive versus HMF relatively far from MCF-DCIS. We have also begun to identify how the HMF become activated and protrusive when co-cultured with MCF-DCIS and to understand the biological function and impact of protrusive HMF during DCIS progression to IDC. We verified that the signaling based on Cathepsin D produced from MCF-DCIS and low-density lipoprotein receptor-related protein-1 (LRP1) from HMF is involved in regulation of the protrusive activity of HMF. Additionally, knocking down LRP1 in HMF inhibited the invasive transition of MCF-DCIS. This study demonstrates one possible route through which MCF-DCIS activate pre-existing fibroblasts and subsequently, leads to the modification of the ECM and the progression to IDC. Citation Format: Kyung Eun Sung, Carolyn Pehlke, Erwin Berthier, Kevin W. Eliceiri, Andreas Friedl, David J. Beebe. A microscale 3-D in vitro model of the breast cancer progression from DCIS to IDC: Deciphering the role of the stromal fibroblasts. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B17.