Extracellular Matrix Dimension and Stiffness Modulate and Remodel Mechano-metabolome of Breast Cancer Cells

The stiffness of the tumor microenvironment (TME) is dynamic and drives metabolic reprogramming in cancer cells as a consequence of tumor progression. To demonstrate the possibility to modulate the mechano-metabolomic profile of breast cancers by tuning the mechanical property and dimensionality of extracellular matrices (ECMs), we cultured triple-negative MDA-MB-231 and luminal MCF-7 cells on 2D and in 3D hydrogels based on tyramine functionalized hyaluronic acid (HTA). Using high-throughput metabolomics analyses, we established that we can differentially regulate breast cancer mechano-metabolome. The stiff hydrogels resulted in upregulated lipid and amino acid metabolism along with increasing malignancy and chemoresistancy. Reprogramming in glucose metabolism is primarily observed in cells seeded on 2D hydrogels, whereas modifications in amino acid metabolism is predominant in cells embedded in 3D stiff hydrogels. These findings suggest that matrix stiffness and dimensions have decisive roles in reprogramming breast cancer metabolome, which is the hallmark of breast cancer development and progression.