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 rag2E450fs (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 BRAFV600E-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.
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This work was supported by Alex’s Lemonade Stand Foundation (J.S.B., M.S.I., D.M.L.), the Live Like Bella Foundation for Childhood Cancer (D.M.L.), American Cancer Society (D.M.L.), the MGH Howard Goodman Fellowship (D.M.L.) and NIH grants R24OD016761, R01CA154923 and U54CA168512. Q.T. is funded by the China Scholarship Council. I.M.T. is funded by Fundação para a Ciênca e Tecnologia, Portugal (SFRH/BD/51288/2010).
Tang, Qin; Moore, John C.; Ignatius, Myron S.; Tenente, Inês M.; Hayes, Madeline N.; Garcia, Elaine G.; Torres Yordán, Nora; Bourque, Caitlin; He, Shuning; Blackburn, Jessica S.; Look, A. Thomas; Houvras, Yariv; and Langenau, David M., "Imaging Tumour Cell Heterogeneity Following Cell Transplantation Into Optically Clear Immune-Deficient Zebrafish" (2016). Molecular and Cellular Biochemistry Faculty Publications. 96.