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 () and Siyuan Zheng ()
Additional contact information
Funan He: University of Texas Health Science Center
Abhik M. Bandyopadhyay: University of Texas Health Science Center
Laura J. Klesse: University of Texas Southwestern Medical Center
Anna Rogojina: University of Texas Health Science Center
Sang H. Chun: University of Texas Health Science Center
Erin Butler: University of Texas Southwestern Medical Center
Taylor Hartshorne: University of Texas Southwestern Medical Center
Trevor Holland: University of Texas Health Science Center
Dawn Garcia: University of Texas Health Science Center
Korri Weldon: University of Texas Health Science Center
Luz-Nereida Perez Prado: University of Texas Health Science Center
Anne-Marie Langevin: University of Texas Health Science Center
Allison C. Grimes: University of Texas Health Science Center
Aaron Sugalski: University of Texas Health Science Center
Shafqat Shah: University of Texas Health Science Center
Chatchawin Assanasen: University of Texas Health Science Center
Zhao Lai: University of Texas Health Science Center
Yi Zou: University of Texas Health Science Center
Dias Kurmashev: University of Texas Health Science Center
Lin Xu: University of Texas Southwestern Medical Center
Yang Xie: University of Texas Southwestern Medical Center
Yidong Chen: University of Texas Health Science Center
Xiaojing Wang: University of Texas Health Science Center
Gail E. Tomlinson: University of Texas Health Science Center
Stephen X. Skapek: University of Texas Southwestern Medical Center
Peter J. Houghton: University of Texas Health Science Center
Raushan T. Kurmasheva: University of Texas Health Science Center
Siyuan Zheng: University of Texas Health Science Center

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-43373-1

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