Forty-five patient-derived xenografts capture the clinical and biological heterogeneity of Wilms tumor

Andrew J. Murphy; Xiang Chen; Emilia M. Pinto; Justin S. Williams; Michael R. Clay; Stanley B. Pounds; Xueyuan Cao; Lei Shi; Tong Lin; Geoffrey Neale; Christopher L. Morton; Mary A. Woolard; Heather L. Mulder; Hyea Jin Gil; Jerold E. Rehg; Catherine A. Billups; Matthew L. Harlow; Jeffrey S. Dome; Peter J. Houghton; John Easton; Jinghui Zhang; Rani E. George; Gerard P. Zambetti; Andrew M. Davidoff

doi:10.1038/s41467-019-13646-9

Forty-five patient-derived xenografts capture the clinical and biological heterogeneity of Wilms tumor

Andrew J. Murphy, Xiang Chen, Emilia M. Pinto, Justin S. Williams, Michael R. Clay, Stanley B. Pounds, Xueyuan Cao, Lei Shi, Tong Lin, Geoffrey Neale, Christopher L. Morton, Mary A. Woolard, Heather L. Mulder, Hyea Jin Gil, Jerold E. Rehg, Catherine A. Billups, Matthew L. Harlow, Jeffrey S. Dome, Peter J. Houghton, John EastonJinghui Zhang, Rani E. George, Gerard P. Zambetti, Andrew M. Davidoff

Molecular Medicine

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

1 Scopus citations

Abstract

The lack of model systems has limited the preclinical discovery and testing of therapies for Wilms tumor (WT) patients who have poor outcomes. Herein, we establish 45 heterotopic WT patient-derived xenografts (WTPDX) in CB17 scid^-/- mice that capture the biological heterogeneity of Wilms tumor (WT). Among these 45 total WTPDX, 6 from patients with diffuse anaplastic tumors, 9 from patients who experienced disease relapse, and 13 from patients with bilateral disease are included. Early passage WTPDX show evidence of clonal selection, clonal evolution and enrichment of blastemal gene expression. Favorable histology WTPDX are sensitive, whereas unfavorable histology WTPDX are resistant to conventional chemotherapy with vincristine, actinomycin-D, and doxorubicin given singly or in combination. This WTPDX library is a unique scientific resource that retains the spectrum of biological heterogeneity present in WT and provides an essential tool to test targeted therapies for WT patient groups with poor outcomes.

Original language	English (US)
Article number	5806
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-13646-9
State	Published - Dec 1 2019

ASJC Scopus subject areas

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

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Murphy, A. J., Chen, X., Pinto, E. M., Williams, J. S., Clay, M. R., Pounds, S. B., Cao, X., Shi, L., Lin, T., Neale, G., Morton, C. L., Woolard, M. A., Mulder, H. L., Gil, H. J., Rehg, J. E., Billups, C. A., Harlow, M. L., Dome, J. S., Houghton, P. J., ... Davidoff, A. M. (2019). Forty-five patient-derived xenografts capture the clinical and biological heterogeneity of Wilms tumor. Nature communications, 10(1), [5806]. https://doi.org/10.1038/s41467-019-13646-9

Forty-five patient-derived xenografts capture the clinical and biological heterogeneity of Wilms tumor. / Murphy, Andrew J.; Chen, Xiang; Pinto, Emilia M.; Williams, Justin S.; Clay, Michael R.; Pounds, Stanley B.; Cao, Xueyuan; Shi, Lei; Lin, Tong; Neale, Geoffrey; Morton, Christopher L.; Woolard, Mary A.; Mulder, Heather L.; Gil, Hyea Jin; Rehg, Jerold E.; Billups, Catherine A.; Harlow, Matthew L.; Dome, Jeffrey S.; Houghton, Peter J.; Easton, John; Zhang, Jinghui; George, Rani E.; Zambetti, Gerard P.; Davidoff, Andrew M.

In: Nature communications, Vol. 10, No. 1, 5806, 01.12.2019.

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

Murphy, AJ, Chen, X, Pinto, EM, Williams, JS, Clay, MR, Pounds, SB, Cao, X, Shi, L, Lin, T, Neale, G, Morton, CL, Woolard, MA, Mulder, HL, Gil, HJ, Rehg, JE, Billups, CA, Harlow, ML, Dome, JS, Houghton, PJ, Easton, J, Zhang, J, George, RE, Zambetti, GP & Davidoff, AM 2019, 'Forty-five patient-derived xenografts capture the clinical and biological heterogeneity of Wilms tumor', Nature communications, vol. 10, no. 1, 5806. https://doi.org/10.1038/s41467-019-13646-9

Murphy, Andrew J. ; Chen, Xiang ; Pinto, Emilia M. ; Williams, Justin S. ; Clay, Michael R. ; Pounds, Stanley B. ; Cao, Xueyuan ; Shi, Lei ; Lin, Tong ; Neale, Geoffrey ; Morton, Christopher L. ; Woolard, Mary A. ; Mulder, Heather L. ; Gil, Hyea Jin ; Rehg, Jerold E. ; Billups, Catherine A. ; Harlow, Matthew L. ; Dome, Jeffrey S. ; Houghton, Peter J. ; Easton, John ; Zhang, Jinghui ; George, Rani E. ; Zambetti, Gerard P. ; Davidoff, Andrew M. / Forty-five patient-derived xenografts capture the clinical and biological heterogeneity of Wilms tumor. In: Nature communications. 2019 ; Vol. 10, No. 1.

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title = "Forty-five patient-derived xenografts capture the clinical and biological heterogeneity of Wilms tumor",

abstract = "The lack of model systems has limited the preclinical discovery and testing of therapies for Wilms tumor (WT) patients who have poor outcomes. Herein, we establish 45 heterotopic WT patient-derived xenografts (WTPDX) in CB17 scid-/- mice that capture the biological heterogeneity of Wilms tumor (WT). Among these 45 total WTPDX, 6 from patients with diffuse anaplastic tumors, 9 from patients who experienced disease relapse, and 13 from patients with bilateral disease are included. Early passage WTPDX show evidence of clonal selection, clonal evolution and enrichment of blastemal gene expression. Favorable histology WTPDX are sensitive, whereas unfavorable histology WTPDX are resistant to conventional chemotherapy with vincristine, actinomycin-D, and doxorubicin given singly or in combination. This WTPDX library is a unique scientific resource that retains the spectrum of biological heterogeneity present in WT and provides an essential tool to test targeted therapies for WT patient groups with poor outcomes.",

author = "Murphy, {Andrew J.} and Xiang Chen and Pinto, {Emilia M.} and Williams, {Justin S.} and Clay, {Michael R.} and Pounds, {Stanley B.} and Xueyuan Cao and Lei Shi and Tong Lin and Geoffrey Neale and Morton, {Christopher L.} and Woolard, {Mary A.} and Mulder, {Heather L.} and Gil, {Hyea Jin} and Rehg, {Jerold E.} and Billups, {Catherine A.} and Harlow, {Matthew L.} and Dome, {Jeffrey S.} and Houghton, {Peter J.} and John Easton and Jinghui Zhang and George, {Rani E.} and Zambetti, {Gerard P.} and Davidoff, {Andrew M.}",

note = "Funding Information: This work was supported by the American Lebanese Syrian Associated Charities (ALSAC/St. Jude Children{\textquoteright}s Research Hospital), the American Pediatric Surgical Association Foundation Jay Grosfeld, MD Scholarship (A.J.M.), NCI Cancer Center Support Grant CA21765, Team Path to the Cure Grant (R.E.G.), and NCI U01 grant CA199297 (P.J.H.). The authors thank Samantha Spencer, Karen Rakestraw, Emily Walker, Melanie Lloyd, Scott Olsen, Granger Ridout, Dana Roeber, and the Hartwell Center for Bioin-formatics and Biotechnology at St. Jude for their technical contributions to this manu- script. We also thank Raven Holcomb and the Department of Pathology for their help with the histologic and immunohistochemical studies. We thank Vani Shanker for her review of the manuscript. Finally, we would like to thank Charles Mullighan, Jeffrey Rubnitz, Matthew Lear, the Tissue Resources Committee, and the St. Jude Biorepository for their assistance with identifying and obtaining the primary tumor specimens.",

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AU - Murphy, Andrew J.

AU - Chen, Xiang

AU - Pinto, Emilia M.

AU - Williams, Justin S.

AU - Clay, Michael R.

AU - Pounds, Stanley B.

AU - Cao, Xueyuan

AU - Shi, Lei

AU - Lin, Tong

AU - Neale, Geoffrey

AU - Morton, Christopher L.

AU - Woolard, Mary A.

AU - Mulder, Heather L.

AU - Gil, Hyea Jin

AU - Rehg, Jerold E.

AU - Billups, Catherine A.

AU - Harlow, Matthew L.

AU - Dome, Jeffrey S.

AU - Houghton, Peter J.

AU - Easton, John

AU - Zhang, Jinghui

AU - George, Rani E.

AU - Zambetti, Gerard P.

AU - Davidoff, Andrew M.

N1 - Funding Information: This work was supported by the American Lebanese Syrian Associated Charities (ALSAC/St. Jude Children’s Research Hospital), the American Pediatric Surgical Association Foundation Jay Grosfeld, MD Scholarship (A.J.M.), NCI Cancer Center Support Grant CA21765, Team Path to the Cure Grant (R.E.G.), and NCI U01 grant CA199297 (P.J.H.). The authors thank Samantha Spencer, Karen Rakestraw, Emily Walker, Melanie Lloyd, Scott Olsen, Granger Ridout, Dana Roeber, and the Hartwell Center for Bioin-formatics and Biotechnology at St. Jude for their technical contributions to this manu- script. We also thank Raven Holcomb and the Department of Pathology for their help with the histologic and immunohistochemical studies. We thank Vani Shanker for her review of the manuscript. Finally, we would like to thank Charles Mullighan, Jeffrey Rubnitz, Matthew Lear, the Tissue Resources Committee, and the St. Jude Biorepository for their assistance with identifying and obtaining the primary tumor specimens.

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N2 - The lack of model systems has limited the preclinical discovery and testing of therapies for Wilms tumor (WT) patients who have poor outcomes. Herein, we establish 45 heterotopic WT patient-derived xenografts (WTPDX) in CB17 scid-/- mice that capture the biological heterogeneity of Wilms tumor (WT). Among these 45 total WTPDX, 6 from patients with diffuse anaplastic tumors, 9 from patients who experienced disease relapse, and 13 from patients with bilateral disease are included. Early passage WTPDX show evidence of clonal selection, clonal evolution and enrichment of blastemal gene expression. Favorable histology WTPDX are sensitive, whereas unfavorable histology WTPDX are resistant to conventional chemotherapy with vincristine, actinomycin-D, and doxorubicin given singly or in combination. This WTPDX library is a unique scientific resource that retains the spectrum of biological heterogeneity present in WT and provides an essential tool to test targeted therapies for WT patient groups with poor outcomes.

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