Reversible epigenetic alterations mediate PSMA expression heterogeneity in advanced metastatic prostate cancer

Abstract

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.

Imaging-based characterization of tumoral heterogeneity for personalized cancer treatment

“…In metastatic prostate cancer, the expression of prostate-specific membrane antigen (PSMA) can vary between the different metastases as an expression of intralesional tumor heterogeneity and due to different gene expressions in the tumor cells. PSMA expression in different lesions can be detected by PET-CT [45]. Heterogeneous expression of PSMA in several lesions has the potential for a severe prognosis [46].…”

Characterization of HOXB13 expression patterns in localized and metastatic castration‐resistant prostate cancer

“…Metastatic cancer samples from 52 patients with metastatic castration‐resistant prostate cancer (mCRPC) were collected as part of the Prostate Cancer Donor Program at the University of Washington [24,25]. For each patient, tissue specimens from different metastatic sites (median number of sites per patient 7, range 1–21) were included [24,25]. In addition, a total of 454 non‐prostatic tumor samples representative of urothelial carcinoma of the bladder ( N = 93), colonic adenocarcinoma ( N = 100), gastric adenocarcinoma ( N = 32) [26], a broad spectrum of renal cell carcinomas ( N = 217), germ cell tumors ( N = 7), and melanomas ( N = 5) were included.…”

“…To further validate these in silico RNA expression studies on the protein level, we evaluated HOXB13 expression in 52 patients with advanced mCRPC (581 samples) from the UW-TAN prostate rapid autopsy cohort [21,24,25], which represents an extensively pretreated patient population with prior androgen deprivation and AR signaling inhibitor therapy (supplementary material, Table S4) [20,21,24,25,39,52]. We found reduced HOXB13 H-scores in ARÀ/NE+ and ARÀ/NEÀ tumors compared with AR+/NEÀ (mean differences À97, 95% CI À118 to À76, and À101, 95% CI À137 to À65, both p < 0.001) and increased H-scores in AR+/NE+ tumors compared with AR+/NEÀ (mean difference 21, 95% CI 8.4-33, p = 0.001) (Figure 4D,E).…”

“…Primary prostate cancer samples came from radical prostatectomy specimens (N = 331) and have been described previously [24]. Metastatic cancer samples from 52 patients with metastatic castration-resistant prostate cancer (mCRPC) were collected as part of the Prostate Cancer Donor Program at the University of Washington [24,25]. For each patient, tissue specimens from different metastatic sites (median number of sites per patient 7, range 1-21) were included [24,25].…”

“…To investigate the expression of HOXB13 in advanced metastatic castration-resistant prostate cancer (mCRPC), we initially conducted in silico analyses of HOXB13 transcript levels in 121 LuCaP PDX tissues (Figure 4A), 98 patients with metastatic prostate cancer (185 samples) from the University of Washington Rapid Autopsy Program (Tissue Acquisition Necropsy, UW-TAN) (Figure 4B), and 266 mCRPC patients from the Stand Up To Cancer (SU2C) International Dream Team (270 samples) (Figure 4C) [21,25,30,51]. To contextualize the expression patterns, we divided each cohort into four molecular subgroups based on AR signaling and NE marker expression [20,21].…”