Reprogramming landscape highlighted by dynamic transcriptomes in therapy-induced neuroendocrine differentiation.

Autor:	Asberry AM; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA., Liu S; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.; Indiana University Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA., Nam HS; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA., Deng X; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA., Wan J; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.; Indiana University Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA.; Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA., Hu CD; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA.; Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN, USA.
Jazyk:	angličtina
Zdroj:	Computational and structural biotechnology journal [Comput Struct Biotechnol J] 2022 Oct 27; Vol. 20, pp. 5873-5885. Date of Electronic Publication: 2022 Oct 27 (Print Publication: 2022).
DOI:	10.1016/j.csbj.2022.10.031
Abstrakt:	Metastatic and locally advanced prostate cancer is treated by pharmacological targeting of androgen synthesis and androgen response via androgen signaling inhibitors (ASI), most of which target the androgen receptor (AR). However, ASI therapy invariably fails after 1-2 years. Emerging clinical evidence indicates that in response to ASI therapy, the AR-positive prostatic adenocarcinoma can transdifferentiate into AR-negative neuroendocrine prostate cancer (NEPC) in 17-25 % treated patients, likely through a process called neuroendocrine differentiation (NED). Despite high clinical incidence, the epigenetic pathways underlying NED and ASI therapy-induced NED remain unclear. By utilizing a combinatorial single cell and bulk mRNA sequencing workflow, we demonstrate in a time-resolved manner that following AR inhibition with enzalutamide, prostate cancer cells exhibit immediate loss of canonical AR signaling activity and simultaneous morphological change from epithelial to NE-like (NEL) morphology, followed by activation of specific neuroendocrine (NE)-associated transcriptional programs. Additionally, we observed that activation of NE-associated pathways occurs prior to complete repression of epithelial or canonical AR pathways, a phenomenon also observed clinically via heterogenous AR status in clinical samples. Our model indicates that, mechanistically, ASI therapy induces NED with initial morphological change followed by deactivation of canonical AR target genes and subsequent de-repression of NE-associated target genes, while retaining AR expression and transcriptional shift towards non-canonical AR activity. Coupled with scRNA-seq and CUT&RUN analysis, our model system can provide a platform for screening of potential therapeutic agents that may prevent ASI-induced NED or reverse the NED process. Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (© 2022 The Author(s).)
Databáze:	MEDLINE
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