Mesenchymal stromal cells confer breast cancer doxorubicin resistance by producing hyaluronan

Chemoresistance is a major hurdle in achieving the expected efficacy in cancer patients. Among many possible mechanisms, mesenchymal stromal cells (MSCs), an integral component of the tumor microenvironment, have been shown to drive the development of chemoresistance. However, the detailed mechanism remains elusive. Here, we demonstrate that when coadministered with 4T1 breast cancer cells, MSCs confer resistance to doxorubicin in breast cancer by reducing its intratumoral accumulation. Histological examination revealed that there is a dramatic increase of hyaluronan (HA) in the tumor tissue when MSCs are co-administered. Further analysis revealed that the tumor-associated MSCs in situ express high levels of hyaluronic acid synthase 2 (HAS2) and HA synthesis inhibitor, 4- methylumbelliferone (4-MU), a medication for gallbladder disorders, reversed the doxorubicin resistance. Additionally, when MSCs with HAS2 knockdown was co-administered with 4T1, the resistance to doxorubicin conferred by MSCs was also abrogated. Molecular dynamics simulation indicates that doxorubicin can bind to HA stably, and form strong interactive forces, which hinders its cellular entry. Importantly, we found that in breast cancer patients, high serum HA levels are positively associated with doxorubicin resistance. Our findings thus demonstrate that HA plays a key role in doxorubicin resistance, and targeting HA synthesis may represent a novel strategy to enhance the efficacy of doxorubicin.