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The androgen receptor regulates a druggable translational regulon in advanced prostate cancer [ribosome profiling]

ABSTRACT: The recent advent of highly potent inhibitors of the androgen receptor and androgen biosynthesis has had the unfortunate iatrogenic effect of fueling new lethal prostate cancer phenotypes in patients. In particular, non-neuroendocrine androgen receptor-low castration resistant prostate cancer (AR low CRPC) is increasing in occurrence amongst patients and is uniformly fatal. The mechanisms that promote this phenotype remain poorly understood. Through molecular studies of murine and human models of AR low CRPC, we have identified a new functional interface between the androgen receptor and the translation initiation complex inhibitor 4EBP1. AR directly regulates 4EBP1 expression which translationally represses eIF4F complex formation and a pro-proliferation program. In the context of AR low prostate cancer, de-repression of translation initiation drives the aberrant expression of the pro-proliferation regulon which fuels uncontrolled cell growth. Genetic and pharmacologic inhibition of the downstream eIF4F translation initiation complex reverses the proliferation phenotype in vitro and in vivo. These findings reveal a new previously unrecognized druggable nexus which functionally link the processes of mRNA transcription and translation initiation in a rapidly emerging class of advanced lethal prostate cancer

ORGANISM(S): Mus musculus

PROVIDER: GSE116082 | GEO | 2019/07/31

REPOSITORIES: GEO

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Project description:Advanced prostate cancer is a leading cause of cancer-related deaths in men, in large part due to our poor understanding of advanced castration-resistant prostate cancer (CRPC). This form of prostate cancer is uniformly lethal. Currently, the main treatments against this disease are anti-androgenic therapies; however, CRPC always develops resistance to these therapeutic modalities. Of particular interest is CRPC lacking androgen receptor (AR) activity, or AR-low CRPC. This subtype has dramatically increased in incidence in the past decade. While many studies have identified a complex architecture in the prostate, we still lack a unified view of the cellular interactions and phenotypes that facilitate advanced prostate cancer maintenance and survival, particularly without AR signaling.To better understand the cellular changes that drive CRPC, we harvested prostates from a mouse model of prostate cancer under multiple conditions and performed single-cell RNA sequencing (scRNASeq). Our findings reveal a subset of the epithelial compartment that is primed for AR-low survival during tumorigenesis, as well as a complex basal-driven mechanism to facilitate expansion of this subtype. Androgen deprivation via castration of the mouse modulates this process by increasing proliferation rates in epithelia. In addition, we observe a dramatic increase in immune cell population upon tumorigenesis. We identify this immune influx as pro-tumor and pinpoint unique signaling phenotypes from individual epithelial subtypes, demonstrating a multifaceted process of recruitment and remodeling by the tumor to build a favorable environment. Androgen signaling is also crucial for maintaining these immune populations, and castration dramatically remodels the tumor environment. Finally, we uncover the importance of protein synthesis regulation in maintaining these complex dynamics; inhibiting the eIF4F translation initiation complex leads to decreased epithelial proliferation and immune recruitment. These findings shed new light on the cellular dynamics of advanced prostate cancer and highlight the importance of employing high-throughput technologies to provide a complete picture of the tumor and its microenvironment. Better understanding of the epithelial subtypes involved in tumor growth, as well as their influence on immune populations in the prostate, can lead to new avenues of treatment.

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The androgen receptor regulates a druggable translational regulon in advanced prostate cancer [ribosome profiling]

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