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The bone ecosystem facilitates multiple myeloma relapse and the evolution of heterogeneous drug resistant disease

Author

Listed:
  • Ryan T. Bishop

    (H. Lee Moffitt Cancer Center and Research Institute)

  • Anna K. Miller

    (H. Lee Moffitt Cancer Center and Research Institute)

  • Matthew Froid

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

  • Niveditha Nerlakanti

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

  • Tao Li

    (H. Lee Moffitt Cancer Center and Research Institute)

  • Jeremy S. Frieling

    (H. Lee Moffitt Cancer Center and Research Institute)

  • Mostafa M. Nasr

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

  • Karl J. Nyman

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

  • Praneeth R. Sudalagunta

    (H. Lee Moffitt Cancer Center and Research Institute)

  • Rafael R. Canevarolo

    (H. Lee Moffitt Cancer Center and Research Institute)

  • Ariosto Siqueira Silva

    (H. Lee Moffitt Cancer Center and Research Institute)

  • Kenneth H. Shain

    (H. Lee Moffitt Cancer Center and Research Institute
    H. Lee Moffitt Cancer Center and Research Institute)

  • Conor C. Lynch

    (H. Lee Moffitt Cancer Center and Research Institute)

  • David Basanta

    (H. Lee Moffitt Cancer Center and Research Institute)

Abstract

Multiple myeloma (MM) is an osteolytic malignancy that is incurable due to the emergence of treatment resistant disease. Defining how, when and where myeloma cell intrinsic and extrinsic bone microenvironmental mechanisms cause relapse is challenging with current biological approaches. Here, we report a biology-driven spatiotemporal hybrid agent-based model of the MM-bone microenvironment. Results indicate MM intrinsic mechanisms drive the evolution of treatment resistant disease but that the protective effects of bone microenvironment mediated drug resistance (EMDR) significantly enhances the probability and heterogeneity of resistant clones arising under treatment. Further, the model predicts that targeting of EMDR deepens therapy response by eliminating sensitive clones proximal to stroma and bone, a finding supported by in vivo studies. Altogether, our model allows for the study of MM clonal evolution over time in the bone microenvironment and will be beneficial for optimizing treatment efficacy so as to significantly delay disease relapse.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46594-0
    DOI: 10.1038/s41467-024-46594-0
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    References listed on IDEAS

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    1. Robert Vander Velde & Nara Yoon & Viktoriya Marusyk & Arda Durmaz & Andrew Dhawan & Daria Miroshnychenko & Diego Lozano-Peral & Bina Desai & Olena Balynska & Jan Poleszhuk & Liu Kenian & Mingxiang Ten, 2020. "Resistance to targeted therapies as a multifactorial, gradual adaptation to inhibitor specific selective pressures," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    2. Michelle A. Lawson & Michelle M. McDonald & Natasa Kovacic & Weng Hua Khoo & Rachael L. Terry & Jenny Down & Warren Kaplan & Julia Paton-Hough & Clair Fellows & Jessica A. Pettitt & T. Neil Dear & Els, 2015. "Osteoclasts control reactivation of dormant myeloma cells by remodelling the endosteal niche," Nature Communications, Nature, vol. 6(1), pages 1-15, December.
    3. Javad Salimi Sartakhti & Mohammad Hossein Manshaei & Soroosh Bateni & Marco Archetti, 2016. "Evolutionary Dynamics of Tumor-Stroma Interactions in Multiple Myeloma," PLOS ONE, Public Library of Science, vol. 11(12), pages 1-17, December.
    4. 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.
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