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Mesenchymal stem cell-derived interleukin-28 drives the selection of apoptosis resistant bone metastatic prostate cancer

Author

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  • Jeremy J. McGuire

    (University of South Florida
    H. Lee Moffitt Cancer Center and Research Institute)

  • Jeremy S. Frieling

    (H. Lee Moffitt Cancer Center and Research Institute)

  • Chen Hao Lo

    (University of South Florida
    H. Lee Moffitt Cancer Center and Research Institute)

  • Tao Li

    (H. Lee Moffitt Cancer Center and Research Institute)

  • Ayaz Muhammad

    (H. Lee Moffitt Cancer Center and Research Institute)

  • Harshani R. Lawrence

    (H. Lee Moffitt Cancer Center and Research Institute)

  • Nicholas J. Lawrence

    (H. Lee Moffitt Cancer Center and Research Institute)

  • Leah M. Cook

    (University of Nebraska Medical Center)

  • Conor C. Lynch

    (H. Lee Moffitt Cancer Center and Research Institute)

Abstract

Bone metastatic prostate cancer (PCa) promotes mesenchymal stem cell (MSC) recruitment and their differentiation into osteoblasts. However, the effects of bone-marrow derived MSCs on PCa cells are less explored. Here, we report MSC-derived interleukin-28 (IL-28) triggers prostate cancer cell apoptosis via IL-28 receptor alpha (IL-28Rα)-STAT1 signaling. However, chronic exposure to MSCs drives the selection of prostate cancer cells that are resistant to IL-28-induced apoptosis and therapeutics such as docetaxel. Further, MSC-selected/IL-28-resistant prostate cancer cells grow at accelerated rates in bone. Acquired resistance to apoptosis is PCa cell intrinsic, and is associated with a shift in IL-28Rα signaling via STAT1 to STAT3. Notably, STAT3 ablation or inhibition impairs MSC-selected prostate cancer cell growth and survival. Thus, bone marrow MSCs drive the emergence of therapy-resistant bone metastatic prostate cancer yet this can be disabled by targeting STAT3.

Suggested Citation

  • Jeremy J. McGuire & Jeremy S. Frieling & Chen Hao Lo & Tao Li & Ayaz Muhammad & Harshani R. Lawrence & Nicholas J. Lawrence & Leah M. Cook & Conor C. Lynch, 2021. "Mesenchymal stem cell-derived interleukin-28 drives the selection of apoptosis resistant bone metastatic prostate cancer," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-20962-6
    DOI: 10.1038/s41467-021-20962-6
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    Cited by:

    1. Yuqian Wang & Renqi Huang & Yougong Lu & Mingqi Liu & Ran Mo, 2024. "Immuno-protective vesicle-crosslinked hydrogel for allogenic transplantation," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Ryan T. Bishop & Anna K. Miller & Matthew Froid & Niveditha Nerlakanti & Tao Li & Jeremy S. Frieling & Mostafa M. Nasr & Karl J. Nyman & Praneeth R. Sudalagunta & Rafael R. Canevarolo & Ariosto Siquei, 2024. "The bone ecosystem facilitates multiple myeloma relapse and the evolution of heterogeneous drug resistant disease," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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