Integrative molecular analyses of the MD Anderson prostate cancer patient-derived xenograft (MDA PCa PDX) series Journal Article
| Authors: | Anselmino, N.; Labanca, E.; Shepherd, P. D. A.; Dong, J.; Yang, J.; Song, X.; Nandakumar, S.; Kundra, R.; Lee, C.; Schultz, N.; Zhang, J.; Araujo, J. C.; Aparicio, A. M.; Subudhi, S. K.; Corn, P. G.; Pisters, L. L.; Ward, J. F.; Davis, J. W.; Vazquez, E. S.; Gueron, G.; Logothetis, C. J.; Futreal, A.; Troncoso, P.; Chen, Y.; Navone, N. M. |
| Article Title: | Integrative molecular analyses of the MD Anderson prostate cancer patient-derived xenograft (MDA PCa PDX) series |
| Abstract: | Purpose: Develop and deploy a robust discovery platform that encompasses heterogeneity, clinical annotation, and molecular characterization and overcomes the limited availability of prostate cancer models. This initiative builds on the rich MD Anderson (MDA) prostate cancer (PCa) patient-derived xenograft (PDX) resource to complement existing publicly available databases by addressing gaps in clinically annotated models reflecting the heterogeneity of potentially lethal and lethal prostate cancer. Experimental Design: We performed whole-genome, targeted, and RNA sequencing in representative samples of the same tumor from 44 PDXs derived from 38 patients linked to donor tumor metadata and corresponding organoids. The cohort includes models derived from different morphologic groups, disease states, and involved organ sites (including circulating tumor cells), as well as paired samples representing heterogeneity or stages before and after therapy. Results: The cohort recapitulates clinically reported alterations in prostate cancer genes, providing a data resource for clinical and molecular interrogation of suitable experimental models. Paired samples displayed conserved molecular alteration profiles, suggesting the relevance of other regulatory mechanisms (e.g., epigenomic) influenced by the microenvironment and/or treatment. Transcriptomically, models were grouped on the basis of morphologic classification. DNA damage response-associated mechanisms emerged as differentially regulated between adenocarcinoma and neuroendocrine prostate cancer in a cross-interrogation of PDX/patient datasets. Conclusions:Weaddressed the gap in clinically relevant prostate cancer models through comprehensive molecular characterization of MDA PCa PDXs, providing a discovery platform that integrates with patient data and benchmarked to therapeutically relevant consensus clinical groupings. This unique resource supports robust hypothesis generation and testing from basic, translational, and clinical perspectives. © 2024 American Association for Cancer Research Inc.. All rights reserved. |
| Keywords: | controlled study; gene mutation; human cell; genetics; cisplatin; nonhuman; paclitaxel; lymph node metastasis; adenocarcinoma; mouse; animal; animals; mice; animal tissue; gene expression; gene expression profiling; prevalence; animal experiment; animal model; gene frequency; tumor xenograft; drug screening; pathology; xenograft model antitumor assays; transcriptomics; tumor marker; dna methylation; prostate cancer; prostatic neoplasms; health care quality; gene expression regulation; genome analysis; gene expression regulation, neoplastic; xenograft; messenger rna; sequence alignment; epigenetics; cpg island; prostate tumor; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; fusion gene; real time polymerase chain reaction; upregulation; bicalutamide; computer model; transcriptome; disease exacerbation; pyrosequencing; circulating tumor cell; synaptophysin; tumor microenvironment; wnt signaling; copy number variation; chromogranin a; cabazitaxel; genetic modification; high throughput sequencing; enzalutamide; niraparib; sanger sequencing; humans; human; male; article; whole genome sequencing; rna sequencing; differential gene expression; heterografts; organoid; biomarkers, tumor; pc-3 [human prostate carcinoma] cell line |
| Journal Title: | Clinical Cancer Research |
| Volume: | 30 |
| Issue: | 10 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2024-05-15 |
| Start Page: | 2272 |
| End Page: | 2285 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-23-2438 |
| PUBMED: | 38488813 |
| PROVIDER: | scopus |
| PMCID: | PMC11094415 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding author is MSK author: Yu Chen -- Source: Scopus |
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