Abstract

While the use of next-generation androgen receptor pathway inhibition (ARPI) therapy has significantly increased the survival of patients with metastatic prostate adenocarcinoma (AdPC), several groups have reported a treatment-resistant mechanism, whereby cancer cells can become androgen receptor (AR) indifferent and gain a neuroendocrine (NE)-like phenotype. This subtype of castration-resistant prostate cancer has been termed “treatment-induced castration-resistant neuroendocrine prostate cancer” (CRPC-NE). Recent reports indicate that the overall genomic landscapes of castration-resistant tumors with AdPC phenotypes and CRPC-NE are not significantly altered. However, CRPC-NE tumors have been found to contain a NE-specific pattern throughout their epigenome and splicing transcriptome, which are significantly modified. The molecular mechanisms by which CRPC-NE develops remain unclear, but several factors have been implicated in the progression of the disease. Recently, Ser/Arg repetitive matrix 4 (SRRM4), a neuronal-specific RNA splicing factor that is upregulated in CRPC-NE tumors, has been shown to establish a CRPC-NE-unique splicing transcriptome, to induce a NE-like morphology in AdPC cells, and, most importantly, to transform AdPC cells into CRPC-NE xenografts under ARPI. Moreover, the SRRM4-targeted splicing genes are highly enriched in various neuronal processes, suggesting their roles in facilitating a CRPC-NE program. This article will address the importance of SRRM4-mediated alternative RNA splicing in reprogramming translated proteins to facilitate NE differentiation, survival, and proliferation of cells to establish CRPC-NE tumors. In addition, we will discuss the potential roles of SRRM4 in conjunction with other known pathways and factors important for CRPC-NE development, such as the AR pathway, TP53 and RB1 genes, the FOXA family of proteins, and environmental factors. This study aims to explore the multifaceted functions of SRRM4 and SRRM4-mediated splicing in driving a CRPC-NE program as a coping mechanism for therapy resistance, as well as define future SRRM4-targeted therapeutic approaches for treating CRPC-NE or mitigating its development.

Highlights

  • Prostate cancer (PCa) is not just a singular disease; it is many diseases that are interconnected through molecular, phenotypic, and functional heterogeneity between patients and within the individual

  • Studies have demonstrated that the androgen receptor (AR) pathway can suppress PCa lineage plasticity into NE or other cell lineages, where androgen receptor pathway inhibition (ARPI) can reduce AR-mediated repression of SOX2 and induce BRN2, which in turn positively regulates the expression of SOX2, a fundamental regulator of stemness during embryonic development [47, 90, 91]. These findings suggest a clear role of AR in conferring prostate adenocarcinoma (AdPC) lineage plasticity and that the selection pressure of ARPI is imperative for the development of Castration-Resistant Prostate Cancer (CRPC)-NE

  • As the AR-mediated repression of Ser/Arg repetitive matrix 4 (SRRM4) function is irrelevant in DU 145 cells, we suggest that the aberrant functions of p53 and RB1 in DU 145 cells primes the cells to be more susceptible to SRRM4-driven NE lineage fate determination

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Summary

INTRODUCTION

Prostate cancer (PCa) is not just a singular disease; it is many diseases that are interconnected through molecular, phenotypic, and functional heterogeneity between patients and within the individual. It was recently demonstrated that a new genetically engineered CRPC mouse model with coinactivation of TP53 and PTEN, named NPp53, progresses to either CRPC-Ad tumors with NE foci that are non-proliferative or CRPC tumors explicit with NE differentiation that are highly proliferative, suggesting the importance of active proliferative genes during CRPC progression for the CRPC-NE phenotype to emerge [38] Based on these observations in PCa, we hope that one can appreciate the vast degree of histopathological, molecular, phenotypic, and functional heterogeneity seen within CRPC subtypes and individual NEPC cases. These findings confirm that CRPC heterogeneity develops as a result of survival mechanisms as a means to escape treatments, such as ARPI, either by progressing into AR-driven AdPC, AR “indifferent” CRPC-NE, or double-negative AR-null and NE marker-null PCa tumors

MECHANISMS OF LINEAGE PLASTICITY
Genetic and Epigenetic Modifications Confer Plasticity of PCa Cells
Alternative RNA Splicing Confers Plasticity of PCa Cells
Regulator REST
Splicing of Epigenomic Regulators
CONCLUSION
Findings
AUTHOR CONTRIBUTIONS
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