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Tumor cell-specific bioluminescence platform to identify stroma-induced changes to anticancer drug activity

Nature Medicine volume 16, pages 483–489 (2010)Cite this article

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An Author Correction to this article was published on 14 February 2024

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Abstract

Conventional anticancer drug screening is typically performed in the absence of accessory cells of the tumor microenvironment, which can profoundly alter antitumor drug activity. To address this limitation, we developed the tumor cell–specific in vitro bioluminescence imaging (CS-BLI) assay. Tumor cells (for example, myeloma, leukemia and solid tumors) stably expressing luciferase are cultured with nonmalignant accessory cells (for example, stromal cells) for selective quantification of tumor cell viability, in presence versus absence of stromal cells or drug treatment. CS-BLI is high-throughput scalable and identifies stroma-induced chemoresistance in diverse malignancies, including imatinib resistance in leukemic cells. A stroma-induced signature in tumor cells correlates with adverse clinical prognosis and includes signatures for activated Akt, Ras, NF-κB, HIF-1α, myc, hTERT and IRF4; for biological aggressiveness; and for self-renewal. Unlike conventional screening, CS-BLI can also identify agents with increased activity against tumor cells interacting with stroma. One such compound, reversine, shows more potent activity in an orthotopic model of diffuse myeloma bone lesions than in conventional subcutaneous xenografts. Use of CS-BLI, therefore, enables refined screening of candidate anticancer agents to enrich preclinical pipelines with potential therapeutics that overcome stroma-mediated drug resistance and can act in a synthetic lethal manner in the context of tumor-stroma interactions.

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Figure 1: Stromal cells modify the response of diverse tumor cell types to various agents.
Figure 2: Effect of blocking IL-6 and IL-6 receptor on MM cell co-cultures with BMSCs.
Figure 3: Mechanisms of drug sensitivity modulation in the context of tumor-stroma interactions.
Figure 4: Enhanced activity of reversine in the presence of stromal cells.

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Acknowledgements

Supported by the Dunkin Donuts Rising Stars program at the Dana-Farber Cancer Institute (C.S.M.), the Chambers Medical Foundation (C.S.M. and P.G.R.), the Steven Cobb Foundation (D.W.M., C.S.M.) and US National Institutes of Health grant R01CA050947 (C.S.M. and K.C.A.). We wish to thank T. Libermann and M. Joseph-Bruno (Harvard Institutes of Medicine Genomics Core) for generation of gene expression data and L. Buon for help with bioinformatic analyses.

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Authors and Affiliations

  1. Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Douglas W McMillin, Jake Delmore, Joseph M Negri, D Corey Geer, Steffen Klippel, Nicholas Mitsiades, Robert L Schlossman, Nikhil C Munshi, Paul G Richardson, Kenneth C Anderson & Constantine S Mitsiades

  2. Department of Medical Oncology, Harvard Medical School, Boston, Massachusetts, USA

    Douglas W McMillin, Jake Delmore, Ellen Weisberg, Joseph M Negri, D Corey Geer, Steffen Klippel, Nicholas Mitsiades, Robert L Schlossman, Nikhil C Munshi, James D Griffin, Paul G Richardson, Kenneth C Anderson & Constantine S Mitsiades

  3. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Douglas W McMillin, Jake Delmore, Ellen Weisberg, Joseph M Negri, D Corey Geer, Steffen Klippel, Robert L Schlossman, Nikhil C Munshi, James D Griffin, Paul G Richardson, Kenneth C Anderson & Constantine S Mitsiades

  4. Boston VA Healthcare System, Boston, Massachusetts, USA

    Nikhil C Munshi

  5. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Andrew L Kung

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Contributions

D.W.M. conducted experiments, performed analysis and wrote the manuscript; J.D. conducted experiments, performed analysis; E.W. conducted experiments, performed analysis; J.M.N. conducted experiments, performed analysis; D.C.G. conducted experiments, performed analysis; S.K. generated cell lines; N.M. performed analysis; R.L.S. provided primary tissue samples; N.C.M. provided primary tissue samples; A.L.K. performed analysis and participated in writing the manuscript; J.D.G. provided cell lines; P.G.R. provided primary tissue samples; K.C.A. participated in writing the manuscript; C.S.M. performed analysis, wrote manuscript and supervised the project.

Corresponding author

Correspondence to Constantine S Mitsiades.

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Competing interests

D.W.M. has equity in Axios Biosciences. R.L.S. is on the Speakers Bureau for Millennium and Celgene. K.C.A. is a consultant for Millennium, Celgene and Novartis. C.S.M. has received in the past consultant honoraria from Millennium, Novartis, Bristol-Myers Squibb, Merck, Kosan, Pharmion and Centocor, as well as licensing royalties from PharmaMar. He has also received research funding from Amgen, AVEO Pharma, EMD Serono, Sunesis and Gloucester Pharmaceuticals.

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McMillin, D., Delmore, J., Weisberg, E. et al. Tumor cell-specific bioluminescence platform to identify stroma-induced changes to anticancer drug activity. Nat Med 16, 483–489 (2010). https://doi.org/10.1038/nm.2112

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