@article{348e0147e4ab4b3596dcb5201daaf6fe,
title = "Visualizing Engrafted Human Cancer and Therapy Responses in Immunodeficient Zebrafish",
abstract = "Xenograft cell transplantation into immunodeficient mice has become the gold standard for assessing pre-clinical efficacy of cancer drugs, yet direct visualization of single-cell phenotypes is difficult. Here, we report an optically-clear prkdc−/−, il2rga−/− zebrafish that lacks adaptive and natural killer immune cells, can engraft a wide array of human cancers at 37°C, and permits the dynamic visualization of single engrafted cells. For example, photoconversion cell-lineage tracing identified migratory and proliferative cell states in human rhabdomyosarcoma, a pediatric cancer of muscle. Additional experiments identified the preclinical efficacy of combination olaparib PARP inhibitor and temozolomide DNA-damaging agent as an effective therapy for rhabdomyosarcoma and visualized therapeutic responses using a four-color FUCCI cell-cycle fluorescent reporter. These experiments identified that combination treatment arrested rhabdomyosarcoma cells in the G2 cell cycle prior to induction of apoptosis. Finally, patient-derived xenografts could be engrafted into our model, opening new avenues for developing personalized therapeutic approaches in the future.",
keywords = "SCID, breast cancer, il2rg, immune deficient, melanoma, prkdc, rhabdomyosarcoma, xenograft, zebrafish",
author = "Chuan Yan and Brunson, {Dalton C.} and Qin Tang and Daniel Do and Iftimia, {Nicolae A.} and Moore, {John C.} and Hayes, {Madeline N.} and Welker, {Alessandra M.} and Garcia, {Elaine G.} and Dubash, {Taronish D.} and Xin Hong and Drapkin, {Benjamin J.} and Myers, {David T.} and Sarah Phat and Angela Volorio and Marvin, {Dieuwke L.} and Matteo Ligorio and Lyle Dershowitz and McCarthy, {Karin M.} and Karabacak, {Murat N.} and Fletcher, {Jonathan A.} and Sgroi, {Dennis C.} and Iafrate, {John A.} and Shyamala Maheswaran and Dyson, {Nick J.} and Haber, {Daniel A.} and Rawls, {John F.} and Langenau, {David M.}",
note = "Funding Information: We thank Dr. Cyril Benes for helpful discussions and feedback on the work and Florence Lin at the Shriners Hospital for Children—Boston Special Shared Mass Spectrometry Facility for help with mass spectrometry studies. We thank Drs. Michael Dyer and Elizabeth Stewart and the The Childhood Solid Tumor Network (CSTN) from St. Jude Children's Research Hospital for patient-derived xenograft models. This work is supported by NIH grants R24OD016761 (D.M.L.), R01CA154923 (D.M.L.), R01CA215118, (D.M.L.), R01CA211734 (D.M.L.), R01CA226926 (D.M.L.), R01CA1299933 (D.A.H.); the Liddy Shriver Sarcoma Initiative (D.M.L. and J.A.F.); the MGH Research Scholars Program (D.M.L.); Shriners Hospital for Children (M.N.K.); U01CA220323 (N.J.D.); HHMI (D.A.H.); National Foundation for Cancer Research (D.A.H.); Breast Cancer Foundation (D.A.H.); the Breast Cancer Research Foundation (D.C.B.); the Lung Cancer Research Foundation (B.J.D.); ASCO Young Investigator Award (B.J.D.); the Tosteson & Fund for Medical Discovery Fellowship from MGH (C.Y.); and the Alex's Lemonade Stand Foundation Young Investigator Award (C.Y.). C.Y. and D.M.L. conceived, designed, and conducted the study; analyzed data; and prepared the manuscript. C.Y. Q.T. D.C.B. and D.D. performed most of the experiments. J.C.M. M.N.H. A.M.W. E.G.G. T.D.D. X.H. A.V. D.L.M. and L.D. assisted with experimental design and execution. B.J.D. D.T.M. and S.P. performed mice studies. M.N.K. performed mass spectrometry studies. K.M.M. and N.A.I. performed genotyping and fish maintenance. J.A.I. performed histopathological analysis. D.C.S. M.L. J.F.R. J.A.F. D.A.H. S.M. and N.J.D. provided important intellectual contributions, designed experiments, and provided cell lines and/or PDXs. The General Hospital Corporation has a patent pending on the creation and use of immune-compromised zebrafish for engraftment of human cancers. D.M.L. is a co-inventor on patent application number USSN 14/903,940. D.A.H. is on the scientific advisory board for Janssen and co-founder of TorpedoDx. J.A.I. is on the scientific advisory board for ArcherDX, Equity, and Sanofi. Funding Information: We thank Dr. Cyril Benes for helpful discussions and feedback on the work and Florence Lin at the Shriners Hospital for Children—Boston Special Shared Mass Spectrometry Facility for help with mass spectrometry studies. We thank Drs. Michael Dyer and Elizabeth Stewart and the The Childhood Solid Tumor Network (CSTN) from St. Jude Children's Research Hospital for patient-derived xenograft models. This work is supported by NIH grants R24OD016761 (D.M.L.), R01CA154923 (D.M.L.), R01CA215118 , (D.M.L.), R01CA211734 (D.M.L.), R01CA226926 (D.M.L.), R01CA1299933 (D.A.H.); the Liddy Shriver Sarcoma Initiative (D.M.L. and J.A.F.); the MGH Research Scholars Program (D.M.L.); Shriners Hospital for Children (M.N.K.); U01CA220323 (N.J.D.); HHMI (D.A.H.); National Foundation for Cancer Research (D.A.H.); Breast Cancer Foundation (D.A.H.); the Breast Cancer Research Foundation (D.C.B.); the Lung Cancer Research Foundation (B.J.D.); ASCO Young Investigator Award (B.J.D.); the Tosteson & Fund for Medical Discovery Fellowship from MGH (C.Y.); and the Alex{\textquoteright}s Lemonade Stand Foundation Young Investigator Award (C.Y.). Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = jun,
day = "13",
doi = "10.1016/j.cell.2019.04.004",
language = "English (US)",
volume = "177",
pages = "1903--1914.e14",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "7",
}