Extracellular Fibronectin and Hyaluronic Acid Effects on Tumorigenic Functions of Triple‐Negative Breast Cancer Cells

ABSTRACT The extracellular matrix (ECM) in solid tumors provides structural support and signaling cues to cancer cells. Altered ECM in tumors promotes local invasion of cancer cells, a key step toward metastasis. Engineered tumor models that are used to study cancer invasion often focus on the effects of an individual ECM molecule on specific functions of cancer cells. However, how different components of ECM in a complex tumor model may co‐regulate cancer invasion and the underlying signaling pathways is understudied. We developed a 3D tumor model of triple‐negative breast cancer (TNBC) to study the effects of fibronectin and hyaluronic acid, alone or in combination, on TNBC cell invasion of collagen‐based hydrogels. Our focus on these molecules was due to their significance in breast tumors, disease progression, and association with worse outcomes in patients. Results showed that fibronectin and hyaluronic acid significantly increase collagen invasion of TNBC cells and oncogenic signaling but not in combination, potentially due to differences in the microstructure of the hydrogels. Fibronectin and hyaluronic acid in composite hydrogels also promoted drug resistance and cancer stemness. This study demonstrated the utility of a 3D tumor model for functional and mechanistic studies to define complex effects of ECM in solid cancers.