Background
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 promotes genomic instability and eventually cell invasion. However, there is a lack of biomarkers to predict what patients will transition to a more invasive tumor or how DCIS cells manage to survive in this harsh microenvironment.
Methods
In this work, we have developed a microfluidic model that recapitulates the DCIS microenvironment. In the microdevice, a DCIS model cell line was grown inside a luminal mammary duct model, embedded in a 3D hydrogel with mammary fibroblasts. Cell behavior was monitored by confocal microscopy and optical metabolic imaging. Additionally, metabolite profile was studied by NMR whereas gene expression was analyzed by RT-qPCR. Findings: 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. These genetic changes observed in the model were in good agreement with patient genomic profiles; identifying multiple compounds targeting the affected pathways. In this context, the hypoxia-activated prodrug tirapazamine selectively destroyed hypoxic DCIS cells. Interpretation: The