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Series GSE215653 Query DataSets for GSE215653
Status Public on Oct 28, 2022
Title Reprogramming Landscape Highlighted by Dynamic Transcriptomes in Therapy-induced Neuroendocrine Differentiation [mRNA-seq]
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary 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.
 
Overall design mRNA-seq performed on six samples of LNCaP cells exposed to enzalutamide for 14 days or LNCaP cells exposed to DMSO control. Cells were grown in complete RPMI 1640 in 2D culture dishes, exposed to enzalultamide (or DMSO control), then harvested following trypsin dissociation from plate.
 
Contributor(s) Asberry AM, Liu S, Nam HS, Deng X, Wan J, Hu C
Citation https://doi.org/10.1016/j.csbj.2022.10.031
Submission date Oct 13, 2022
Last update date Oct 28, 2022
Contact name Changdeng Hu
Organization name Purdue University
Department Dept. of Medicinal Chemistry and Molecular Pharmacology
Street address 575 Stadium Mall Drive
City West Lafayette
State/province IN
ZIP/Postal code 47907
Country USA
 
Platforms (1)
GPL24676 Illumina NovaSeq 6000 (Homo sapiens)
Samples (6)
GSM6637903 LNCaP cells, DMSO treatment, 1
GSM6637904 LNCaP cells, DMSO treatment, 2
GSM6637905 LNCaP cells, DMSO treatment, 3
This SubSeries is part of SuperSeries:
GSE215945 Reprogramming Landscape Highlighted by Dynamic Transcriptomes in Therapy-induced Neuroendocrine Differentiation
Relations
BioProject PRJNA890319

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Supplementary file Size Download File type/resource
GSE215653_DE.xlsx 9.6 Mb (ftp)(http) XLSX
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Raw data are available in SRA
Processed data are available on Series record

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