Organotypic Breast Cancer Model Reveals Starvation-Induced Spatial-Temporal Metabolic Adaptations

Ductal carcinoma in situ (DCIS) is the earliest stage of breast cancer. During DCIS,tumor cells remain inside the mammary duct, growing under a microenvironment characterized by hypoxia, nutrient starvation, and waste product accumulation; this harsh microenvironment promote genomic instability and eventually cell invasion. We have developed a microfluidic model that recapitulates those aspects of the DCIS microenvironment. In the microfluidic device, DCIS cells were grown inside a luminal mammary duct model, embedded in a 3D hydrogel with mammary fibroblasts. DCIS cell metabolism led to hypoxia and nutrient starvation; revealing an altered metabolism focused on glycolysis and other hypoxia-associated pathways. In response to this starvation and hypoxia, DCIS cells modified the expression of multiple genes and a gradient of different metabolic phenotypes was observed across the mammary duct model. Upon exposure to the hypoxia-activated prodrug tirapazamine, the DCIS cells located at the lumen core were selectively destroyed, while the normal fibroblasts embedded in the matrix and the epithelial cells located at the lumen periphery were unaffected. In summary, this study provides insight into the metabolic changes that occur during cancer, and introduces a physiologically relevant breast cancer model that can be used to evaluate prospective breast cancer biomarkers and therapeutics.