title: Imaging tumour cell heterogeneity following cell transplantation into optically clear immune-deficient zebrafish.
abstract: Cancers contain a wide diversity of cell types that are defined by differentiation states, genetic mutations and altered epigenetic programmes that impart functional diversity to individual cells. Elevated tumour cell heterogeneity is linked with progression, therapy resistance and relapse. Yet, imaging of tumour cell heterogeneity and the hallmarks of cancer has been a technical and biological challenge. Here we develop optically clear immune-compromised rag2(E450fs) (casper) zebrafish for optimized cell transplantation and direct visualization of fluorescently labelled cancer cells at single-cell resolution. Tumour engraftment permits dynamic imaging of neovascularization, niche partitioning of tumour-propagating cells in embryonal rhabdomyosarcoma, emergence of clonal dominance in T-cell acute lymphoblastic leukaemia and tumour evolution resulting in elevated growth and metastasis in BRAF(V600E)-driven melanoma. Cell transplantation approaches using optically clear immune-compromised zebrafish provide unique opportunities to uncover biology underlying cancer and to dynamically visualize cancer processes at single-cell resolution in vivo.
authors.affiliation: Molecular Pathology, Cancer Center, and Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts 02129, USA.|Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02139, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Tang
authors.affiliation: Molecular Pathology, Cancer Center, and Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts 02129, USA.|Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02139, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Moore
authors.affiliation: Molecular Pathology, Cancer Center, and Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts 02129, USA.|Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02139, USA.
authors.forename: Myron S
authors.initials: MS
authors.lastname: Ignatius
authors.affiliation: Molecular Pathology, Cancer Center, and Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts 02129, USA.|Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02139, USA.|Abel Salazar Biomedical Sciences Institute, University of Porto, Porto 4099-003, Portugal.
authors.forename: Inês M
authors.initials: IM
authors.lastname: Tenente
authors.affiliation: Molecular Pathology, Cancer Center, and Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts 02129, USA.|Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02139, USA.
authors.forename: Madeline N
authors.initials: MN
authors.lastname: Hayes
authors.affiliation: Molecular Pathology, Cancer Center, and Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts 02129, USA.|Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02139, USA.
authors.forename: Elaine G
authors.initials: EG
authors.lastname: Garcia
authors.affiliation: Molecular Pathology, Cancer Center, and Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts 02129, USA.|Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02139, USA.
authors.forename: Nora
authors.initials: N
authors.lastname: Torres Yordán
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York, New York 10065, USA.|Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Bourque
authors.affiliation: Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02139, USA.|Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Shuning
authors.initials: S
authors.lastname: He
authors.affiliation: Molecular Pathology, Cancer Center, and Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts 02129, USA.|Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02139, USA.|Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky 40506, USA.
authors.forename: Jessica S
authors.initials: JS
authors.lastname: Blackburn
authors.affiliation: Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02139, USA.|Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: A Thomas
authors.initials: AT
authors.lastname: Look
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York, New York 10065, USA.|Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA.
authors.forename: Yariv
authors.initials: Y
authors.lastname: Houvras
authors.affiliation: Molecular Pathology, Cancer Center, and Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts 02129, USA.|Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02139, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Langenau
mesh_terms: D000818:Animals; D058948:Cell Tracking / Q000295:instrumentation / Q000379:methods*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D016867:Immunocompromised Host; D008545:Melanoma / Q000737:chemistry* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000276:immunology
chemical_list: D004268:DNA-Binding Proteins; C583227:RAG2 protein, zebrafish; D029961:Zebrafish Proteins