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Mesenchymal stromal cells confer breast cancer doxorubicin resistance by producing hyaluronan

Oncogene volume 42, pages 3221–3235 (2023)Cite this article

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Abstract

Chemotherapy resistance represents a major cause of therapeutic failure and mortality in cancer patients. Mesenchymal stromal cells (MSCs), an integral component of tumor microenvironment, are known to promote drug resistance. However, the detailed mechanisms remain to be elucidated. Here, we found that MSCs confer breast cancer resistance to doxorubicin by diminishing its intratumoral accumulation. Hyaluronan (HA), a major extracellular matrix (ECM) product of MSCs, was found to mediate the chemoresistant effect. The chemoresistant effect of MSCs was abrogated when hyaluronic acid synthase 2 (HAS2) was depleted or inhibited. Exogenous HA also protected tumor grafts from doxorubicin. Molecular dynamics simulation analysis indicates that HA can bind with doxorubicin, mainly via hydrophobic and hydrogen bonds, and thus reduce its entry into breast cancer cells. This mechanism is distinct from the reported chemoresistant effect of HA via its receptor on cell surface. High HA serum levels were also found to be positively associated with chemoresistance in breast cancer patients. Our findings indicate that the HA-doxorubicin binding dynamics can confer cancer cells chemoresistance. Reducing HA may enhance chemotherapy efficacy.

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Fig. 1: MSCs protect breast cancer cells from doxorubicin.
Fig. 2: MSCs supernatant reduces doxorubicin content in breast cancer cells.
Fig. 3: Hyaluronan produced by MSCs protects cancer cells from doxorubicin.
Fig. 4: HA mediates the doxorubicin resistant effect of MSCs in vivo.
Fig. 5: HA impedes cellular entry of doxorubicin through direct binding.
Fig. 6: 4-MU strengthens antitumor effects of doxorubicin, pirarubicin and epirubicin.
Fig. 7: Association of HA levels with chemoresistance in breast cancer patients.
Fig. 8: A schematic model depicting the mechanism by which HA secreted from MSCs confer breast cancer doxorubicin resistance.

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All original data are available from the authors under request

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Acknowledgements

This study was supported by grants from National Natural Science Foundation of China (81930085, 31961133024, 32150710523, 31900635, 82202032), the National Key R&D Program of China (2021YFA110060), Jiangsu Province International Joint Laboratory for Regenerative Medicine Fund, State Key Laboratory of Radiation Medicine and Protection, Soochow University (GZN1201902) and Suzhou Foreign Academician Workstation Fund (SWY20220). We especially thank Dr. Jian Jin for providing expert technical assistance in molecular dynamics simulation.

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Authors and Affiliations

  1. The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China

    Zhanhong Liu, Pengbo Hou, Jiankai Fang, Rui Liu, Yayun Ding, Muqiu Zuo, Peishan Li, Lijuan Cao, Chao Feng, Changshun Shao & Yufang Shi

  2. Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Rome, Italy

    Zhanhong Liu, Pengbo Hou, Rui Liu & Gerry Melino

  3. School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, Jiangsu, China

    Jingyu Zhu

  4. Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China

    Juanmin Zha

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Contributions

ZHL: conception and design, collection and assembly of data, animal experiments, data analysis and interpretation, and manuscript writing. PBH, JKF: conception and design, data analysis and interpretation. JY Zhu: molecular dynamics simulations, data analysis and interpretation. JM Zha and YYD: contribution of key reagents. RL, MQZ, LJC and CF: animal experiments. PSL and GM: data analysis and interpretation. CSS and YFS: conception and design, manuscript writing, administrative support and financial support. All authors read and approved the final manuscript.

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Correspondence to Changshun Shao or Yufang Shi.

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Liu, Z., Hou, P., Fang, J. et al. Mesenchymal stromal cells confer breast cancer doxorubicin resistance by producing hyaluronan. Oncogene 42, 3221–3235 (2023). https://doi.org/10.1038/s41388-023-02837-w

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