Sulfated Hyaluronan Drives Cell Adaptation and Matrix Composition in Advanced 3D Breast Cancer Cell Models

Hyaluronan (HA), a major extracellular matrix (ECM) glycosaminoglycan, plays a key role in breast cancer progression. Although native HA lacks sulfate groups, chemically modified sulfated hyaluronan (sHA) has demonstrated promising antitumor activity. Previous work from our group showed that sHA alters cellular functions and modulates ECM-related gene expression in triple-negative breast cancer (TNBC) cells. The aim of this study was to investigate the effects of low-molecular-weight HA (50 kDa) and its sulfated derivative of the same molecular weight, sHA, in MDA-MB-231 and MCF-7 breast cancer cells using advanced 3D cell culture models. Gene expression analyses focused on ECM components, including HA receptors and matrix metalloproteinases (MMPs) that were evaluated. The 3D cell morphology was examined using scanning electron microscopy (SEM). Spheroid growth and expression profiles linked to ECM remodeling and invasiveness were also assessed. Notably, sHA significantly inhibited 3D spheroid growth, reduced cell spreading in a cell line-dependent manner and influenced the expression of genes correlated with ECM remodeling and HA synthesis. These findings emphasize the importance of 3D models for studying ECM-driven breast cancer progression, further supporting sHA as a potential therapeutic modulator.