Co-cultures of iPSC-derived Mammary-like Organoids and Patient-derived Microtumors Model Invasive Behavior of Breast Cancer ex vivo

Abstract

Background Tumor-adjacent benign mammary epithelium and myoepithelium can play a pivotal role in tumor growth and progression. We investigated the invasive behavior of patient-derived microtumors and breast cancer cell line-derived spheroids in co-culture with induced pluripotent stem cell-derived mammary-like organoids in an autologous and allogenic manner. This co-culture systems enables a better understanding of the tumor-promoting function of the benign mammary (myo-) epithelium in different types of breast cancers. Methods Using three-dimensional co-culture settings of induced pluripotent stem cell-derived mammary-like organoids and patient-derived microtumors or cancer cell line-derived spheroids, we investigated tumor growth and invasiveness of the cancers by using imaging-based analysis. Levels of Fibronectin and Metalloproteinase-2 in co-cultures and respective mono-cultures were measured using multiplexed Luminex assay. Results We observed significant increases in growth and invasiveness of invasive ductal carcinoma of no special type patient-derived microtumors in co-culture with induced pluripotent stem cell-derived mammary-like organoids. We identified upregulations of the prognostic markers Fibronectin and Metalloproteinase-2 in all co-cultures compared to respective mono-cultures of mammary-like organoids, patient-derived microtumors and cell line-derived spheroids. Conclusions These findings indicate a tumor-promoting role of the tumor-adjacent mammary (myo-) epithelium dependent on the tumor composition and tumor stage. Our results highlight the importance of breast tumor models that closely resemble the heterogenous composition of primary breast tumors.