Genomic profiling of subcutaneous patient-derived xenografts reveals immune constraints on tumor evolution in childhood solid cancer

Funan He; Abhik M Bandyopadhyay; Laura J. Klesse; Anna Rogojina; Sang H. Chun; Erin Butler; Taylor Hartshorne; Trevor Holland; Dawn Garcia; Korri Weldon; Luz Nereida Perez Prado; Anne Marie Langevin; Allison C. Grimes; Aaron Sugalski; Shafqat Shah; Chatchawin Assanasen; Zhao Lai; Yi Zou; Dias Kurmashev; Lin Xu; Yang Xie; Yidong Chen; Xiaojing Wang; Gail E. Tomlinson; Stephen X. Skapek; Peter J. Houghton; Raushan T. Kurmasheva; Siyuan Zheng

doi:10.1038/s41467-023-43373-1

Genomic profiling of subcutaneous patient-derived xenografts reveals immune constraints on tumor evolution in childhood solid cancer

Funan He, Abhik M Bandyopadhyay, Laura J. Klesse, Anna Rogojina, Sang H. Chun, Erin Butler, Taylor Hartshorne, Trevor Holland, Dawn Garcia, Korri Weldon, Luz Nereida Perez Prado, Anne Marie Langevin, Allison C. Grimes, Aaron Sugalski, Shafqat Shah, Chatchawin Assanasen, Zhao Lai, Yi Zou, Dias Kurmashev, Lin XuYang Xie, Yidong Chen, Xiaojing Wang, Gail E. Tomlinson, Stephen X. Skapek, Peter J. Houghton, Raushan T. Kurmasheva, Siyuan Zheng

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Abstract

Subcutaneous patient-derived xenografts (PDXs) are an important tool for childhood cancer research. Here, we describe a resource of 68 early passage PDXs established from 65 pediatric solid tumor patients. Through genomic profiling of paired PDXs and patient tumors (PTs), we observe low mutational similarity in about 30% of the PT/PDX pairs. Clonal analysis in these pairs show an aggressive PT minor subclone seeds the major clone in the PDX. We show evidence that this subclone is more immunogenic and is likely suppressed by immune responses in the PT. These results suggest interplay between intratumoral heterogeneity and antitumor immunity may underlie the genetic disparity between PTs and PDXs. We further show that PDXs generally recapitulate PTs in copy number and transcriptomic profiles. Finally, we report a gene fusion LRPAP1-PDGFRA. In summary, we report a childhood cancer PDX resource and our study highlights the role of immune constraints on tumor evolution.

Original language	English (US)
Article number	7600
Journal	Nature communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-43373-1
State	Published - Dec 2023

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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He, F., Bandyopadhyay, A. M., Klesse, L. J., Rogojina, A., Chun, S. H., Butler, E., Hartshorne, T., Holland, T., Garcia, D., Weldon, K., Prado, L. N. P., Langevin, A. M., Grimes, A. C., Sugalski, A., Shah, S., Assanasen, C., Lai, Z., Zou, Y., Kurmashev, D., ... Zheng, S. (2023). Genomic profiling of subcutaneous patient-derived xenografts reveals immune constraints on tumor evolution in childhood solid cancer. Nature communications, 14(1), Article 7600. https://doi.org/10.1038/s41467-023-43373-1

He, F, Bandyopadhyay, AM, Klesse, LJ, Rogojina, A, Chun, SH, Butler, E, Hartshorne, T, Holland, T, Garcia, D, Weldon, K, Prado, LNP, Langevin, AM , Grimes, AC , Sugalski, A, Shah, S, Assanasen, C , Lai, Z, Zou, Y, Kurmashev, D, Xu, L, Xie, Y, Chen, Y , Wang, X , Tomlinson, GE, Skapek, SX, Houghton, PJ , Kurmasheva, RT & Zheng, S 2023, 'Genomic profiling of subcutaneous patient-derived xenografts reveals immune constraints on tumor evolution in childhood solid cancer', Nature communications, vol. 14, no. 1, 7600. https://doi.org/10.1038/s41467-023-43373-1

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abstract = "Subcutaneous patient-derived xenografts (PDXs) are an important tool for childhood cancer research. Here, we describe a resource of 68 early passage PDXs established from 65 pediatric solid tumor patients. Through genomic profiling of paired PDXs and patient tumors (PTs), we observe low mutational similarity in about 30% of the PT/PDX pairs. Clonal analysis in these pairs show an aggressive PT minor subclone seeds the major clone in the PDX. We show evidence that this subclone is more immunogenic and is likely suppressed by immune responses in the PT. These results suggest interplay between intratumoral heterogeneity and antitumor immunity may underlie the genetic disparity between PTs and PDXs. We further show that PDXs generally recapitulate PTs in copy number and transcriptomic profiles. Finally, we report a gene fusion LRPAP1-PDGFRA. In summary, we report a childhood cancer PDX resource and our study highlights the role of immune constraints on tumor evolution.",

author = "Funan He and Bandyopadhyay, {Abhik M} and Klesse, {Laura J.} and Anna Rogojina and Chun, {Sang H.} and Erin Butler and Taylor Hartshorne and Trevor Holland and Dawn Garcia and Korri Weldon and Prado, {Luz Nereida Perez} and Langevin, {Anne Marie} and Grimes, {Allison C.} and Aaron Sugalski and Shafqat Shah and Chatchawin Assanasen and Zhao Lai and Yi Zou and Dias Kurmashev and Lin Xu and Yang Xie and Yidong Chen and Xiaojing Wang and Tomlinson, {Gail E.} and Skapek, {Stephen X.} and Houghton, {Peter J.} and Kurmasheva, {Raushan T.} and Siyuan Zheng",

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doi = "10.1038/s41467-023-43373-1",

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AU - He, Funan

AU - Bandyopadhyay, Abhik M

AU - Klesse, Laura J.

AU - Rogojina, Anna

AU - Chun, Sang H.

AU - Butler, Erin

AU - Hartshorne, Taylor

AU - Holland, Trevor

AU - Garcia, Dawn

AU - Weldon, Korri

AU - Prado, Luz Nereida Perez

AU - Langevin, Anne Marie

AU - Grimes, Allison C.

AU - Sugalski, Aaron

AU - Shah, Shafqat

AU - Assanasen, Chatchawin

AU - Lai, Zhao

AU - Zou, Yi

AU - Kurmashev, Dias

AU - Xu, Lin

AU - Xie, Yang

AU - Chen, Yidong

AU - Wang, Xiaojing

AU - Tomlinson, Gail E.

AU - Skapek, Stephen X.

AU - Houghton, Peter J.

AU - Kurmasheva, Raushan T.

AU - Zheng, Siyuan

PY - 2023/12

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N2 - Subcutaneous patient-derived xenografts (PDXs) are an important tool for childhood cancer research. Here, we describe a resource of 68 early passage PDXs established from 65 pediatric solid tumor patients. Through genomic profiling of paired PDXs and patient tumors (PTs), we observe low mutational similarity in about 30% of the PT/PDX pairs. Clonal analysis in these pairs show an aggressive PT minor subclone seeds the major clone in the PDX. We show evidence that this subclone is more immunogenic and is likely suppressed by immune responses in the PT. These results suggest interplay between intratumoral heterogeneity and antitumor immunity may underlie the genetic disparity between PTs and PDXs. We further show that PDXs generally recapitulate PTs in copy number and transcriptomic profiles. Finally, we report a gene fusion LRPAP1-PDGFRA. In summary, we report a childhood cancer PDX resource and our study highlights the role of immune constraints on tumor evolution.

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Genomic profiling of subcutaneous patient-derived xenografts reveals immune constraints on tumor evolution in childhood solid cancer

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