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XactMice: humanizing mouse bone marrow enables microenvironment reconstitution in a patient-derived xenograft model of head and neck cancer

Oncogene volume 35, pages 290–300 (2016)Cite this article

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Abstract

The limitations of cancer cell lines have led to the development of direct patient-derived xenograft models. However, the interplay between the implanted human cancer cells and recruited mouse stromal and immune cells alters the tumor microenvironment and limits the value of these models. To overcome these constraints, we have developed a technique to expand human hematopoietic stem and progenitor cells (HSPCs) and use them to reconstitute the radiation-depleted bone marrow of a NOD/SCID/IL2rg−/− (NSG) mouse on which a patient’s tumor is then transplanted (XactMice). The human HSPCs produce immune cells that home into the tumor and help replicate its natural microenvironment. Despite previous passage on nude mice, the expression of epithelial, stromal and immune genes in XactMice tumors aligns more closely to that of the patient tumor than to those grown in non-humanized mice—an effect partially facilitated by human cytokines expressed by both the HSPC progeny and the tumor cells. The human immune and stromal cells produced in the XactMice can help recapitulate the microenvironment of an implanted xenograft, reverse the initial genetic drift seen after passage on non-humanized mice and provide a more accurate tumor model to guide patient treatment.

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Acknowledgements

We thank the patients and normal subjects for their time and generous tissue and blood donations. This work was primarily supported by Department of Defense Award W81XWN-10-1-0798 (principal investigator AJ; co-investigator YR), the Charles C Gates Center for Regenerative Medicine and Stem Cell Biology, and National Institutes of Health Cancer Center Support Grant P30 CA046934 (AJ, YR). Additionally supported by NIH R21 DE019712 (AJ), NIH R01 CA149456 (AJ), the Janet Mordecai Foundation (AJ), the Peter and Rhonda Grant Foundation (AJ), NIH R01 CA117802-06 (YR), NIH P30 AR057212-02 (YR), NIH P01 AI022295-24 (YR), NIH T32 CA174648 (principal investigator XJW; co-investigator PNL) and a Translational Research Award from the Leukemia and Lymphoma Society (YR).

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Author notes

  1. J J Morton and G Bird: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine,

    J J Morton, S B Keysar, D P Astling, T R Lyons, R T Anderson, M J Glogowska, J R Eagles, P N Le, B McGettigan, N Padilla-Just, M Varella-Garcia, D W Bowles, P Schedin, A-C Tan & A Jimeno

  2. Department of Dermatology, University of Colorado School of Medicine,

    G Bird, P Estes, D R Roop & Y Refaeli

  3. Department of Biostatistics and Informatics, University of Colorado School of Medicine,

    D P Astling & A-C Tan

  4. Department of Radiation Oncology, University of Colorado School of Medicine,

    G Gan

  5. Department of Pathology, University of Colorado School of Medicine,

    P Fernandez & X-J Wang

  6. Department of Otolaryngology, University of Colorado School of Medicine,

    J I Song & A Jimeno

  7. Charles C. Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado School of Medicine, Aurora, CO, USA

    D R Roop, X-J Wang, Y Refaeli & A Jimeno

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  1. J J Morton
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Corresponding authors

Correspondence to Y Refaeli or A Jimeno.

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Competing interests

AJ, YR, XJW and DRR are co-inventors of technology presented in this report. The remainig authors declare no conflict of interest.

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Morton, J., Bird, G., Keysar, S. et al. XactMice: humanizing mouse bone marrow enables microenvironment reconstitution in a patient-derived xenograft model of head and neck cancer. Oncogene 35, 290–300 (2016). https://doi.org/10.1038/onc.2015.94

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