Abstract 4526: Tumor invasion and escape from an engineered solid-like aggregate of human breast cancer cells into a cavity
Authors: Kourouklis Andreas P. , Ghani Usman , Han Siyang , Dance Yoseph , Simi Allison K. , Tien Joe , Nelson Celeste M. 
Published: August 2019

Abstract
The mechanical properties of the tumor microenvironment (TME) play a critical role on the progression of breast cancer metastasis. However, the complex architecture of the TME conceals the individual effects of different biophysical and biochemical factors on tumor invasion and intravasation. To investigate this question, we engineered a robust breast tumor model of solid-like 3D aggregate of human breast cancer cells with interstitial fluid pressure (IFP), and further integrated it with an empty cavity to emulate the presence of an impaired capillary vessel. In brief, we embed MDA-MB-231 human breast cancer cells in one of two neighboring collagen type I cavities that are molded within polydimethylsiloxane (PDMS) channels. This multicellular aggregate is subject to selected gradients of hydrostatic pressure through opposing reservoirs of culture media that are located at the base (Pbase) and the tip (Ptip) of the tumor. We found that breast cancer cells disseminate from the multicellular aggregate and escape into the proximal cavity under Ptip &gt; Pbase. The separation distance between the aggregate and the cavity influences the features of tumor escape. Tumor models that were seeded within a distance of less than 150 μm from the cavity demonstrated significantly shorter time (t1/2~ 4 days) for the escape of 50% of the tumor population than those seeded between 150 and 300 μm. In contrast, less than 50% of the tumors that were seeded longer than 300 μm apart of the cavity successfully escaped after ~ 2 weeks under Ptip &gt; Pbase. In addition, we found that cells escaped into the cavity through three major modes: a) single-cell migration, b) multicellular invasion, and c) tumor growth. Single-cell migration was the dominant route of escape in collagen gels of low concentration (2.5 mg/ml). In contrast, tumor growth and multicellular invasion were the dominant modes of escape in collagen gels of high concentration (4mg/ml). Moreover, the tumor invasions were found to be preferentially directed normal to the surface of the tumor, and to be drastically eliminated in effect of pharmacological inhibition of matrix metalloproteinases (MMPs). These preliminary findings will be put together with additional quantitative studies to correlate tumor-cavity separation with the different modes of tumor escape. Overall, our engineered breast tumor model composes a unique platform to investigate the biophysical and biochemical mechanisms of the tumor microenvironment that drive tumor invasion and intravasation into the circulatory system.
Citation Format: Andreas P. Kourouklis, Usman Ghani, Siyang Han, Yoseph Dance, Allison K. Simi, Joe Tien, Celeste M. Nelson. Tumor invasion and escape from an engineered solid-like aggregate of human breast cancer cells into a cavity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4526.