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Conditionally reprogrammed cells from patient-derived xenograft to model neuroendocrine prostate cancer development

ABSTRACT: Treatment-emergent neuroendocrine prostate cancer (t-NEPC) is a lethal subtype of advanced prostate cancer that develops via NE transdifferentiation of prostate adenocarcinomas in response to androgen receptor (AR)-inhibition therapy. Study of t-NEPC has been hampered by a lack of clinically relevant models. We previously established a unique and first-in-field patient-derived xenograft (PDX) model of adenocarcinoma (LTL331)-to-NEPC (LTL331R) transdifferentiation. In this study, we applied conditional reprogramming (CR) culture to establish a LTL331 PDX-derived cancer cell line named LTL331_CR_Cell. LTL331_CR_Cells retain the same genomic mutations as the LTL331 parental tumor, can be continuously propagated in vitro, and can be genetically manipulated. Androgen deprivation treatment on LTL331_CR_Cells showed no effect on cell proliferation. Transcriptomic analyses comparing the LTL331_CR_Cell to its parental tumor revealed a profound downregulation of the androgen response pathway and an upregulation of stem and basal cell marker genes. The transcriptome of LTL331_CR_Cells partially resembles that of post-castrated LTL331 xenografts in mice. Notably, when grafted under the renal capsule of male NOD/SCID mice, LTL331_CR_Cells spontaneously give rise to NEPC tumors as manifested by the histological expression of the NE marker CD56 and the loss of adenocarcinoma markers such as PSA. Transcriptomic analyses of the newly developed NEPC tumors further demonstrate marked enrichment of NEPC signature genes and loss of AR signaling genes. This study provides a novel research tool based on a unique PDX model. It allows for the investigation of mechanisms underlying t-NEPC development by enabling gene manipulation ex vivo and subsequent functional evaluation in vivo.

ORGANISM(S): Homo sapiens

PROVIDER: GSE149091 | GEO | 2020/06/19

REPOSITORIES: GEO

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Project description:Histone deacetylation is crucial for the regulation of chromatin structure, gene transcription and the epigenetic state of the cell. With the emergence of the neuroendocrine (NE) phenotype in castration-resistant prostate cancer (CRPC), we hypothesized that the inhibition of HDAC1/2 would disrupt the epigenetic events involved in the conversion of prostate adenocarcinoma to a NE prostate cancer (NEPC) phenotype. Additionally, monotherapies tend to have limited efficacy in cancer treatment and combination treatments show more promise. Since the PI3K/AKT/mTOR pathway is a well-established tumor growth-promoting pathway and a promising target in CRPC and NEPC, we investigated the tumor suppressing activities of fimepinostat, a dual HDAC and PI3K inhibitor, on both prostate adenocarcinoma and NEPC. We evaluated multiple cell lines and patient-derived xenograft (PDX) models of prostate adenocarcinoma and NEPC to determine the roles of HDAC1/2 and AKT inhibition, both individually and in combination, in suppressing CRPC and NEPC tumor growth in vitro and in vivo. HDAC1/2 inhibition in combination with PI3K/AKT inhibition was more efficacious than targeting each pathway alone, induced growth inhibitory effects (in some cases synergistic) through cell cycle inhibition and apoptosis across an array of prostate adenocarcinoma and NEPC patient-derived xenografts (PDX) and cell lines in vitro and in vivo. Molecular profiling revealed on-target effects of combined HDAC1/2 and PI3K/AKT inhibition as well as a common downregulation of Myc, E2F, DNA repair, and G2M checkpoint targets, independent of prostate cancer phenotype. Fimepinostat therapy was also associated with the suppression of lineage transcription factor expression including androgen receptor (AR) in prostate adenocarcinoma and Achaete-scute homolog 1 (ASCL1) in NEPC. Our findings demonstrate that dual HDAC1/2 and PI3K/AKT pathway inhibition leads to robust tumor growth inhibition in both adenocarcinoma and NEPC, suggesting that fimepinostat may represent a novel therapeutic for both prostate adenocarcinoma and NEPC phenotypes of CRPC.

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Conditionally reprogrammed cells from patient-derived xenograft to model neuroendocrine prostate cancer development

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