(137g) Matrix Stiffness and Interstitial Flow Regulate Breast Cancer Malignancy in a Tumor-Microenvironment-on-a-Chip (TMOC) System

In the past 50 years, extensive studies have explored the different mechanical and chemical cues that regulate tumor malignancy. Based on these studies, numerous attempts have been made to replicate the tumor microenvironment in a high-throughput lab-scale system. Such a “tumor-microenvironment-on-a-chip (TMOC)” would greatly reduce the time and costs associated with cancer drug screening. Many TMOC-like systems have been prepared with mechanical and chemical properties similar to those in the in vivo tumor environment. To date, however, no TMOC system has been prepared with both tunable interstitial flow and matrix stiffness—two key parameters known to regulate cancer malignancy. To this end, we embedded breast cancer cells in a collagen matrix with varying degrees of stiffness, ranging from that of healthy tissue to that of cancerous tissue. These breast cancer cells were then cultured for 6 days with or without a continuous interstitial flow, and cancer malignancy upregulation was determined by measuring the downregulation of estrogen receptor-alpha (ER-alpha). More specifically, the downregulation of ER-alpha is commonly associated with a luminal-to-basal transition in breast cancer cells, which is a key biomarker for aggressive breast cancer. Cancer cells in the cancer tissue-like gel had significantly lower ER-alpha expression than cells grown in the healthy tissue-like gels, independent of interstitial flow. Interestingly enough, for cells in the healthy tissue-like gel, the presence of flow led to a higher level of ER-alpha, suggesting that some amount of mechanical flow will prevent a luminal-to-basal transition.  For future studies, we will incorporate additional growth factors and cells to complete the tumor microenvironment, in turn creating a precision TMOC system.