Reversible epigenetic alterations mediate PSMA expression heterogeneity in advanced metastatic prostate cancer.
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ABSTRACT:
PROVIDER: PRJNA843461 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19441362_1.fastq.gz | Fastqsanger.gz | |||
| SRR19441362_2.fastq.gz | Fastqsanger.gz | |||
| SRR19441363_1.fastq.gz | Fastqsanger.gz | |||
| SRR19441363_2.fastq.gz | Fastqsanger.gz | |||
| SRR19441364_1.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: Prostate-specific membrane antigen (PSMA) is a cell surface protein expressed in prostate cancer. PSMA targeted imaging and therapeutic approaches have shown clinical benefit, but there are limited data on the heterogeneity of PSMA tissue expression in metastatic castration-resistant prostate cancer (mCRPC) and the mechanisms involved in regulating PSMA expression are not well understood. Results: PSMA expression differed across molecular subtypes of CRPC. In a rapid autopsy cohort in which multiple metastatic sites per patient were sampled, we found that 13/52 (25%) of cases had no PSMA detected and 24/52 (46%) showed heterogeneous PSMA expression between individual metastases. Of these 52 cases, 35 (67%) cases harbored at least one PSMA negative metastatic site. Transcriptomic analyses of PSMA negative tumors revealed distinct differences relative to PSMA-positive tumors including expression of several drug targets. DNA methylation studies showed a tight correlation between CpG methylation and PSMA expression. Treatment with histone deacetylase (HDAC) and DNA methyl transferase (DNMT) inhibitors restored of PSMA expression in vitro and in vivo. Conclusions: Here, we document the extent of PSMA expression diversity in CRPC, highlight novel targeting approaches for PSMA-negative tumors and propose strategies to overcome resistance to PSMA-directed therapies. Collectively, these data can help to guide the clinical development of PSMA targeting agents for diagnosis and therapy.
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Project description:Prostate-specific membrane antigen (PSMA) is an important cell surface target in prostate cancer. There are limited data on the heterogeneity of PSMA tissue expression in metastatic castration-resistant prostate cancer (mCRPC). Furthermore, the mechanisms regulating PSMA expression (encoded by the FOLH1 gene) are not well understood. Here, we demonstrate that PSMA expression is heterogeneous across different metastatic sites and molecular subtypes of mCRPC. In a rapid autopsy cohort in which multiple metastatic sites per patient were sampled, we found that 13 of 52 (25%) cases had no detectable PSMA and 23 of 52 (44%) cases showed heterogeneous PSMA expression across individual metastases, with 33 (63%) cases harboring at least 1 PSMA-negative site. PSMA-negative tumors displayed distinct transcriptional profiles with expression of druggable targets such as MUC1. Loss of PSMA was associated with epigenetic changes of the FOLH1 locus, including gain of CpG methylation and loss of histone 3 lysine 27 (H3K27) acetylation. Treatment with histone deacetylase (HDAC) inhibitors reversed this epigenetic repression and restored PSMA expression in vitro and in vivo. Collectively, these data provide insights into the expression patterns and regulation of PSMA in mCRPC and suggest that epigenetic therapies - in particular, HDAC inhibitors - can be used to augment PSMA levels.
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Project description:Prostate-specific membrane antigen (PSMA) has emerged as an important therapeutic target in metastatic castration-resistant prostate cancer (CRPC). However, not all patients respond to PSMA-targeted therapy, in part due to heterogeneity of tumor expression of the target PSMA. Furthermore, loss of PSMA expression develops in up to 15-20% of patients with CRPC, and the underlying mechanisms remain poorly defined. In this study, we developed an orthotopic xenograft model of CRPC using 22Rv1 cell line, we observed lower PSMA expression in liver lesions versus other sites of metastatic disease, suggesting a potential role of the microenvironment in modulating PSMA expression. To facilitate investigation of PSMA-suppression, we cultured and immortalized a liver metastasis of 22Rv1 metastatic xenograft model in vitro as a new cell line (22Rv1-LMD) which remained AR-positive and PSMA-negative.
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Project description:Prostate-specific membrane antigen (PSMA) has emerged as an important therapeutic target in metastatic castration-resistant prostate cancer (CRPC). However, not all patients respond to PSMA-targeted therapy, in part due to heterogeneity of tumor expression of the target PSMA. Furthermore, loss of PSMA expression develops in up to 15-20% of patients with CRPC, and the underlying mechanisms remain poorly defined. In this study, we developed an orthotopic xenograft model of CRPC using 22Rv1 cell line, we observed lower PSMA expression in liver lesions versus other sites of metastatic disease, suggesting a potential role of the microenvironment in modulating PSMA expression. To facilitate investigation of PSMA-suppression, we cultured and immortalized a liver metastasis of 22Rv1 metastatic xenograft model in vitro as a new cell line (22Rv1-LMD) which remained AR-positive and PSMA-negative.
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Project description:Prostate-specific membrane antigen (PSMA) has emerged as an important therapeutic target in metastatic castration-resistant prostate cancer (CRPC). However, not all patients respond to PSMA-targeted therapy, in part due to heterogeneity of tumor expression of the target PSMA. Furthermore, loss of PSMA expression develops in up to 15-20% of patients with CRPC, and the underlying mechanisms remain poorly defined. In this study,To investigate possible epigenetic regulation of PSMA in the context of HOXB13-independent PSMA-suppressed tumors, we performed ChIPseq to evaluate the activation mark Histone H3 Lysine 27 acetylation (H3K27ac) on our previously characterized organoids. Similar to AR-positive, PSMA-positive 22Rv1 cells, the AR-negative, PSMA-positive NEPC model WCM1262 demonstrated H3K27ac at the PSMA (FOLH1) gene promotor corresponding with high PSMA expression, whereas other PSMA-negative NEPC models demonstrated low H3K27ac.
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