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

Nat Commun. 2023 Nov 22;14(1):7600. doi: 10.1038/s41467-023-43373-1.

Authors

Funan He^#^{1

2}, Abhik M Bandyopadhyay^#¹, Laura J Klesse^{3

4

5}, Anna Rogojina¹, Sang H Chun⁶, Erin Butler^{3

4

5}, Taylor Hartshorne³, Trevor Holland¹, Dawn Garcia¹, Korri Weldon¹, Luz-Nereida Perez Prado¹, Anne-Marie Langevin^{7

8}, Allison C Grimes^{1

7}, Aaron Sugalski⁷, Shafqat Shah⁷, Chatchawin Assanasen^{7

8}, Zhao Lai^{1

8

9}, Yi Zou¹, Dias Kurmashev¹, Lin Xu^{3

4

10}, Yang Xie^{4

10

11}, Yidong Chen^{1

2

8}, Xiaojing Wang^{1

2

8}, Gail E Tomlinson^{1

7

8}, Stephen X Skapek^{3

4

5}, Peter J Houghton^{1

8

9}, Raushan T Kurmasheva^{12

13

14}, Siyuan Zheng^{15

16

17}

Affiliations

¹ Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX, USA.
² Department of Population Health Sciences, University of Texas Health Science Center, San Antonio, TX, USA.
³ Department of Pediatrics, Division of Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁴ Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁵ Gill Center for Cancer and Blood Disorders, Children's Health Children's Medical Center, Dallas, TX, USA.
⁶ Department of Biochemistry and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA.
⁷ Department of Pediatrics, University of Texas Health Science Center, San Antonio, TX, USA.
⁸ Mays Cancer Center, University of Texas Health Science Center, San Antonio, TX, USA.
⁹ Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, USA.
¹⁰ Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹¹ Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹² Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX, USA. kurmasheva@uthscsa.edu.
¹³ Mays Cancer Center, University of Texas Health Science Center, San Antonio, TX, USA. kurmasheva@uthscsa.edu.
¹⁴ Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, USA. kurmasheva@uthscsa.edu.
¹⁵ Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX, USA. zhengs3@uthscsa.edu.
¹⁶ Department of Population Health Sciences, University of Texas Health Science Center, San Antonio, TX, USA. zhengs3@uthscsa.edu.
¹⁷ Mays Cancer Center, University of Texas Health Science Center, San Antonio, TX, USA. zhengs3@uthscsa.edu.

^# Contributed equally.

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.

MeSH terms

Animals
Child
Disease Models, Animal
Genomics / methods
Heterografts
Humans
Mutation
Neoplasms* / genetics
Neoplasms* / pathology
Transcriptome / genetics
Xenograft Model Antitumor Assays

Abstract

MeSH terms

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