Imaging tumour cell heterogeneity following cell transplantation into optically clear immune-deficient zebrafish

Qin Tang; John C. Moore; Myron S. Ignatius; Inês M. Tenente; Madeline N. Hayes; Elaine G. Garcia; Nora Torres Yordán; Caitlin Bourque; Shuning He; Jessica S. Blackburn; A. Thomas Look; Yariv Houvras; David M. Langenau

doi:10.1038/ncomms10358

Imaging tumour cell heterogeneity following cell transplantation into optically clear immune-deficient zebrafish

Qin Tang, John C. Moore, Myron S. Ignatius, Inês M. Tenente, Madeline N. Hayes, Elaine G. Garcia, Nora Torres Yordán, Caitlin Bourque, Shuning He, Jessica S. Blackburn, A. Thomas Look, Yariv Houvras, David M. Langenau

Molecular and Cellular Biochemistry

Research output: Contribution to journal › Article › peer-review

70 Scopus citations

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.

Original language	English
Article number	10358
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms10358
State	Published - Jan 21 2016

Bibliographical note

Funding Information:
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 Fundac¸ão para a Ciênca e Tecnologia, Portugal (SFRH/BD/51288/2010). We thank the Specialized Histopathology Services at Massachusetts General Hospital and the Dana-Farber/Harvard Cancer Center (P30 CA06516), Massachusetts General Hospital Cancer Center/Molecular Pathology Confocal Core and the Harvard Center for Biological Imaging for technical support; Drs Fabrice Laroche and Hui Feng for helpful suggestions; Brian Millet and Anthony Sinagra for helpful statistical advice.

Funding Information:
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 Cienca e Tecnologia, Portugal (SFRH/BD/51288/2010). We thank the Specialized Histopathology Services at Massachusetts General Hospital and the Dana-Farber/Harvard Cancer Center (P30 CA06516), Massachusetts General Hospital Cancer Center/Molecular Pathology Confocal Core and the Harvard Center for Biological Imaging for technical support; Drs Fabrice Laroche and Hui Feng for helpful suggestions; Brian Millet and Anthony Sinagra for helpful statistical advice.

ASJC Scopus subject areas

Chemistry (all)
Biochemistry, Genetics and Molecular Biology (all)
Physics and Astronomy (all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ncomms10358

Cite this

Tang, Q., Moore, J. C., Ignatius, M. S., Tenente, I. M., Hayes, M. N., Garcia, E. G., Torres Yordán, N., Bourque, C., He, S., Blackburn, J. S., Look, A. T., Houvras, Y., & Langenau, D. M. (2016). Imaging tumour cell heterogeneity following cell transplantation into optically clear immune-deficient zebrafish. Nature Communications, 7, Article 10358. https://doi.org/10.1038/ncomms10358

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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.",

author = "Qin Tang and Moore, {John C.} and Ignatius, {Myron S.} and Tenente, {In{\^e}s M.} and Hayes, {Madeline N.} and Garcia, {Elaine G.} and {Torres Yord{\'a}n}, Nora and Caitlin Bourque and Shuning He and Blackburn, {Jessica S.} and Look, {A. Thomas} and Yariv Houvras and Langenau, {David M.}",

note = "Funding Information: This work was supported by Alex{\textquoteright}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 Fundac¸{\~a}o para a Ci{\^e}nca e Tecnologia, Portugal (SFRH/BD/51288/2010). We thank the Specialized Histopathology Services at Massachusetts General Hospital and the Dana-Farber/Harvard Cancer Center (P30 CA06516), Massachusetts General Hospital Cancer Center/Molecular Pathology Confocal Core and the Harvard Center for Biological Imaging for technical support; Drs Fabrice Laroche and Hui Feng for helpful suggestions; Brian Millet and Anthony Sinagra for helpful statistical advice. Funding Information: 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 Funda{\c c}{\~a}o para a Cienca e Tecnologia, Portugal (SFRH/BD/51288/2010). We thank the Specialized Histopathology Services at Massachusetts General Hospital and the Dana-Farber/Harvard Cancer Center (P30 CA06516), Massachusetts General Hospital Cancer Center/Molecular Pathology Confocal Core and the Harvard Center for Biological Imaging for technical support; Drs Fabrice Laroche and Hui Feng for helpful suggestions; Brian Millet and Anthony Sinagra for helpful statistical advice.",

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doi = "10.1038/ncomms10358",

language = "English",

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TY - JOUR

T1 - Imaging tumour cell heterogeneity following cell transplantation into optically clear immune-deficient zebrafish

AU - Tang, Qin

AU - Moore, John C.

AU - Ignatius, Myron S.

AU - Tenente, Inês M.

AU - Hayes, Madeline N.

AU - Garcia, Elaine G.

AU - Torres Yordán, Nora

AU - Bourque, Caitlin

AU - He, Shuning

AU - Blackburn, Jessica S.

AU - Look, A. Thomas

AU - Houvras, Yariv

AU - Langenau, David M.

N1 - Funding Information: 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 Fundac¸ão para a Ciênca e Tecnologia, Portugal (SFRH/BD/51288/2010). We thank the Specialized Histopathology Services at Massachusetts General Hospital and the Dana-Farber/Harvard Cancer Center (P30 CA06516), Massachusetts General Hospital Cancer Center/Molecular Pathology Confocal Core and the Harvard Center for Biological Imaging for technical support; Drs Fabrice Laroche and Hui Feng for helpful suggestions; Brian Millet and Anthony Sinagra for helpful statistical advice. Funding Information: 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 Cienca e Tecnologia, Portugal (SFRH/BD/51288/2010). We thank the Specialized Histopathology Services at Massachusetts General Hospital and the Dana-Farber/Harvard Cancer Center (P30 CA06516), Massachusetts General Hospital Cancer Center/Molecular Pathology Confocal Core and the Harvard Center for Biological Imaging for technical support; Drs Fabrice Laroche and Hui Feng for helpful suggestions; Brian Millet and Anthony Sinagra for helpful statistical advice.

PY - 2016/1/21

Y1 - 2016/1/21

N2 - 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.

AB - 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.

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U2 - 10.1038/ncomms10358

DO - 10.1038/ncomms10358

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JO - Nature Communications

JF - Nature Communications

M1 - 10358

ER -

Imaging tumour cell heterogeneity following cell transplantation into optically clear immune-deficient zebrafish

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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