Abstract: Metastasis is the leading cause of breast cancer-related deaths and driven by invasion, but how cancer stem-like cells (CSCs) and their metabolic phenotype regulate breast cancer invasion remains unclear. Using microfluidic invasion models, metabolomics, and computational flux balance analysis (FBA), we investigated the functional links between the stem-like, metabolic, and invasive phenotype of breast cancer cells. Our results suggest that CSCs are more invasive than non-CSCs and that broad metabolic changes associated with overproduction of hyaluronic acid (HA) rather than transcriptional changes caused by hypoxia-inducible factor α (HIF1α)-related signaling play a role in this process. Accordingly, overexpression of hyaluronic acid synthases (HAS) 2 or 3 induced a breast cancer metabolic phenotype that promoted stemness and invasion. These changes were clinically significant as a gene signature defined by HAS2/3 overexpression correlated with increased invasion and was predictive of worse patient survival. Collectively, this study suggests that HA overproduction enabled by metabolic reprogramming negatively influences prognosis in breast cancer patients by enhancing stemness and invasion and expands the current paradigm implicating HIF1α signaling as the major driver of these processes.

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