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A Unique System of Paired PDX Models to Investigate the Progression of Potentially Lethal to Lethal Prostate Tumors at a Multi-omic Level

ABSTRACT: Prostate cancer (PCa) exhibits substantial heterogeneity in aggressiveness among patients, with significant lethality in its advanced metastatic stages. Defining the molecular mechanisms underlying rapid disease progression remains a pressing unmet need. Here, we present a comparative analysis of a longitudinally paired patient-derived xenograft model of aggressive PCa progression before and after therapeutic intervention. Using multi-omic analysis, we characterized the MDA PCa 177-B (androgen receptor [AR]-negative, basal) and MDA PCa 189-1 (AR-positive, luminal) models, which exhibit distinct transcriptomic profiles yet originate from a shared clonal lineage. Targeted and single-cell DNA sequencing revealed that these models share 71.5% of copy number variations, tracing back to a common ancestral cell population. Targeted bisulfite sequencing of both models revealed epigenetic marks unique for aggressive disease compared to normal/benign prostate. Next, through single-cell RNA sequencing, we identified a subset of cells exhibiting a low differentiation profile, present in both PDX models and characterized by a unique molecular signature associated with adaptive immune responses and metastasis-related pathways. Further integrative analysis using data from a broad spectrum of disease samples demonstrated that, within this pair of aggressive PDX models, these low-differentiation clusters are exclusive to stem-like tumor cell populations. These findings support the hypothesis that a continuum of epigenetic, transcriptomic, and phenotypic transitions occurs during the progression of PCa from its potentially lethal to lethal stages. We suggest that this continuum can be captured through well-characterized, longitudinal PDX models derived from the same patient. Our multi-omic approach underscores the value of such models in uncovering the dynamic and adaptive mechanisms of PCa aggressiveness.

ORGANISM(S): Homo sapiens

PROVIDER: GSE293911 | GEO | 2026/04/05

REPOSITORIES: GEO

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Project description:Purpose: Small-cell prostate carcinoma (SCPC) morphology predicts for a distinct clinical behavior, resistance to androgen ablation, and frequent but short responses to chemotherapy. The model systems we report reflect the biology of the human disease and can be used to improve our understanding of SCPC and to develop new therapeutic strategies for it. Experimental Design: We developed a set of CRPC xenografts and examined their fidelity to their human tumors of origin. We compared the expression and genomic profiles of SCPC and large cell neuroendocrine carcinoma (LCNEC) xenografts to those of typical prostate adenocarcinoma xenografts and used a panel of 60 human tumors to validate our findings using immunohistochemistry. Results: We show that SCPC and LCNEC xenograft models retain high fidelity to their human tumors of origin and are characterized by a marked upregulation of UBE2C and other M-phase cell cycle genes in the absence of AR, retinoblastoma (RB1) and cyclin D1 (CCND1) expression and confirm these findings in a panel of CRPC patients’ samples. In addition, array comparative genomic hybridization of the xenografts showed that the SCPC/LCNEC tumors display more copy number variations than the adenocarcinoma counterparts and that there is amplification of the UBE2C locus and microdeletions of RB1 in a subset of these, but no AR nor CCND1 deletions. Moreover, the AR, RB1, and CCND1 promoters showed no CpG methylation in the SCPC xenografts. Conclusion: Modeling human prostate cancer with xenografts allows in-depth and detailed studies of its underlying biology. The detailed clinical annotation of the donor tumors enables associations of anticipated relevance to be made. Futures studies in the xenografts will address the functional significance of the findings. 22 samples were analysed, that included MDA PCa 79 (n = 3), 117-9 (n = 3), 130 (n = 2), 144-4 (n = 4), 144-13 (n = 5), 146-10 (n = 3), 155-2 (n = 1), and 155-12 (n = 1). MDA PCA 79, 117-9 and 130 samples had the pathologic characteristics of prostate adenocarcinoma and were compared against MDA PCA 144-4, 144-13, 146-10 and 155-12 that have the pathologic features of prostate small cell/ large cell neuroendocrine carcinoma

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A Unique System of Paired PDX Models to Investigate the Progression of Potentially Lethal to Lethal Prostate Tumors at a Multi-omic Level

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