Comprehensive analysis of androgen receptor status in prostate cancer with neuroendocrine differentiation

Abstract

The androgen receptor (AR) signaling is a key contributor to tumorigenesis and the progression of prostate cancer. A subset of patients may develop neuroendocrine (NE) features, resulting in resistance to androgen deprivation therapy and poor prognosis. In this study, we combined immunostaining and bulk and single-cell transcriptome analyses to better characterize the status of AR in prostate cancer with neuroendocrine differentiation. The exploration of online datasets indicated the existence of ARHIGH/NEHIGH prostate cancer and revealed that these double-high cases are majorly present in castration-resistant prostate cancer with a less neuroendocrine-transdifferentiated state. We then reviewed 8,194 prostate cancer cases with available immunohistochemistry reports and found 2.3% cases (n = 189) that showed at least one of the NE markers (chromogranin A, synaptophysin, and neural cell adhesion molecule 1) being positive in at least 5% of epithelial cells. Within these 189 cases, we observed that 81.0% cases (n = 153) showed AR positive and 19.0% (n = 36) showed AR negative. Patients with AR loss tumors demonstrated a correlation with adverse clinical stages, indicating a trade-off between AR and advanced disease in neuroendocrine differentiation. Using multiplex immunofluorescence staining, we observed the co-localization of AR and NE markers in prostate cancer cells. In addition, data mining of single-cell transcriptome further confirmed the existence of ARHIGH/NEHIGH prostate cancer cells in castration-resistant samples and suggested that AR still exerts its androgen response and anti-apoptotic effect in these double-high cells. Thus, our study provides a better understanding of AR signaling in the cellular plasticity of prostate cancer with neuroendocrine differentiation and allows new insights into the therapeutic development.

Preclinical Models of Neuroendocrine Prostate Cancer

“…The acquisition of aggressive features results in a high rate of visceral metastases and poor prognosis (Conteduca et al., 2019). Neuroendocrine tumors are generally defined by the expression of chromogranin A (CHGA), synaptophysin (SYP), neural cell adhesion molecule 1 (NCAM1), and enolase 2 (ENO2; Epstein et al., 2014; Su et al., 2022). In recent years, an increasing effort is being made to understand the specific markers that characterize neuroendocrine prostate tumors.…”

MALAT1 promotes FOXA1 degradation by competitively binding to miR-216a-5p and enhancing neuroendocrine differentiation in prostate cancer

“…3 A). Evidence exists reporting that AR, a ligand-activated transcription factor, is a driver of prostate carcinogenesis due to its function in modulating the NED of PC [ 4 , 11 , 12 ].

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“…Tumors acquire the ability to metastasize from adenocarcinoma to neuroendocrine subtypes [ 7 , 8 ]. Furthermore, decreased AR expression and signal transduction support in PC cells can increase neuroendocrine (NE) differentiation (NED) in PC and is correlated with invasive phenotypes [ 4 , [9] , [10] , [11] , [12] ].…”

Prognostic Significance of Chromogranin A Expression in the Initial and Second Biopsies in Metastatic Prostate Cancer

“…Neuroendocrine differentiation in PCa may arise via lineage plasticity, with clonal evolution from either primary PCa or CRPC cells [30]. Single-cell transcriptome sequencing also demonstrated the existence of AR HIGH /NE HIGH prostate cancer cells in hormone-naïve prostate cancer cohorts [31]. The precise definition of this clinical state is still lacking, but the expression of NE markers usually confers more aggressive clinical behavior [7,32], which typically bears alterations in RB1, TP53, PTEN and AR [33].…”