Abstract 3215: Microenvironmental impact on breast cancer cell dormancy and drug sensitivity in a 3D model
Authors: Han Bo , Fang Josephine , Tan Shih-Jye , Wu Yi-Chen 
Published: August 2015

Abstract
Solid tumor contains heterogeneous and complex extracellular matrix environment. Tumor phenotypes are highly dependent on complex interactions with the surrounding cells and the ECM. Tumor dormancy is commonly observed clinically, however, the sources of dormant cells are unknown and their biological properties unclear. Recent evidence suggests that tumor residues are always ECM associated. Ioundt is important to replicate in vivo tumor environment with defined extracellular matrix in 3D environment to study tumor cell distinctive states. In this study, we engineered a construct by using transglutaminase crosslinked gelatin to recapitulate the in vivo breast cancer milieu and mimicking distinctive density of breast cancer matrix. First, we found that 3D matrix restriction had significant impacts on proliferation rate, cell morphology, tumoroid size and protein expressions of breast cancer cell MDA-MB-23 when growing in 3D matrices with different stiffness. Besides MDA-MB-231, ten different other tumor cell types were placed in a spectrum of gel conditions and their proliferation profiles have been established. We therefore could setup tumor culture models specifically for proliferative or dormant cells by changing gel concentration or crosslinking rates. Second, we used exogenous collagenase to mimic autocrine or paracrine proteases activity to mimic ECM degradation in dynamic tumor progression. We found that alteration of matrix mechanical restriction by enzyme degradation or ECM deposition could reversibly induce breast cancer cell from dormancy to proliferative or vise versa. Third, we tested the drug sensitivity at different matrix conditions. Both paclitaxel and gemcitabine displayed significant efficacy when cells in the highly proliferative state. However, paclitaxel had strong impact on breaking up tumor clusters but with little effect on inducing their apoptosis. Gemcitabine could diffuse into different size cell clusters to induce apoptosis. When cells were adopted dormant state, they showed less drug sensitivity for both drugs. We further demonstrate that there was no additive effect of paclitaxel and gemcitabine at all tested conditions. In conclusion, we setup a tailorable 3D model to study tumor cell proliferative and dormant states by taking into consideration of cell type preference on ECM conditions. There is an urgent need for tools to reliably and quickly predict responses of patients’ cancers to treatment regimens. With this in vitro drug screening model, it has potential to predict the drugs in single use or in combination effect.
Note: This abstract was not presented at the meeting.
Citation Format: Bo Han, Josephine Fang, Shih-Jye Tan, Yi-Chen Wu. Microenvironmental impact on breast cancer cell dormancy and drug sensitivity in a 3D model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3215. doi:10.1158/1538-7445.AM2015-3215