title: XactMice: humanizing mouse bone marrow enables microenvironment reconstitution in a patient-derived xenograft model of head and neck cancer.
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.
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine.
authors.forename: J J
authors.initials: JJ
authors.lastname: Morton
authors.affiliation: Department of Dermatology, University of Colorado School of Medicine.
authors.forename: G
authors.initials: G
authors.lastname: Bird
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine.
authors.forename: S B
authors.initials: SB
authors.lastname: Keysar
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine.|Department of Biostatistics and Informatics, University of Colorado School of Medicine.
authors.forename: D P
authors.initials: DP
authors.lastname: Astling
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine.
authors.forename: T R
authors.initials: TR
authors.lastname: Lyons
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine.
authors.forename: R T
authors.initials: RT
authors.lastname: Anderson
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine.
authors.forename: M J
authors.initials: MJ
authors.lastname: Glogowska
authors.affiliation: Department of Dermatology, University of Colorado School of Medicine.
authors.forename: P
authors.initials: P
authors.lastname: Estes
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine.
authors.forename: J R
authors.initials: JR
authors.lastname: Eagles
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine.
authors.forename: P N
authors.initials: PN
authors.lastname: Le
authors.affiliation: Department of Radiation Oncology, University of Colorado School of Medicine.
authors.forename: G
authors.initials: G
authors.lastname: Gan
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine.
authors.forename: B
authors.initials: B
authors.lastname: McGettigan
authors.affiliation: Department of Pathology, University of Colorado School of Medicine.
authors.forename: P
authors.initials: P
authors.lastname: Fernandez
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine.
authors.forename: N
authors.initials: N
authors.lastname: Padilla-Just
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine.
authors.forename: M
authors.initials: M
authors.lastname: Varella-Garcia
authors.affiliation: Department of Otolaryngology, University of Colorado School of Medicine.
authors.forename: J I
authors.initials: JI
authors.lastname: Song
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine.
authors.forename: D W
authors.initials: DW
authors.lastname: Bowles
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine.
authors.forename: P
authors.initials: P
authors.lastname: Schedin
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine.|Department of Biostatistics and Informatics, University of Colorado School of Medicine.
authors.forename: A-C
authors.initials: AC
authors.lastname: Tan
authors.affiliation: Department of Dermatology, University of Colorado School of Medicine.|Charles C. Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Roop
authors.affiliation: Department of Pathology, University of Colorado School of Medicine.|Charles C. Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: X-J
authors.initials: XJ
authors.lastname: Wang
authors.affiliation: Department of Dermatology, University of Colorado School of Medicine.|Charles C. Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Refaeli
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine.|Department of Otolaryngology, University of Colorado School of Medicine.|Charles C. Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: A
authors.initials: A
authors.lastname: Jimeno
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D006801:Humans; D051379:Mice; D059016:Tumor Microenvironment / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: D016207:Cytokines