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Updated: Sep 22, 2025
Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019
Chromatin profiles classify castration-resistant prostate cancers suggesting therapeutic targets
Fanying Tang1,2, Duo Xu1,2,3,4, Shangqian Wang5,6
1Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA.
Abstract:
In castration-resistant prostate cancer (CRPC), the loss of androgen receptor (AR) dependence leads to clinically aggressive tumors with few therapeutic options. We used ATAC-seq (assay for transposase-accessible chromatin sequencing), RNA-seq, and DNA sequencing to investigate 22 organoids, six patient-derived xenografts, and 12 cell lines. We identified the well-characterized AR-dependent and neuroendocrine subtypes, as well as two AR-negative/low groups: a Wnt-dependent subtype, and a stem cell-like (SCL) subtype driven by activator protein-1 (AP-1) transcription factors. We used transcriptomic signatures to classify 366 patients, which showed that SCL is the second most common subtype of CRPC after AR-dependent. Our data suggest that AP-1 interacts with the YAP/TAZ and TEAD proteins to maintain subtype-specific chromatin accessibility and transcriptomic landscapes in this group. Together, this molecular classification reveals drug targets and can potentially guide therapeutic decisions.
Insights
Castration-resistant prostate cancer (CRPC) has new subtypes identified, including a stem cell-like (SCL) group driven by activator protein-1 (AP-1). This molecular classification reveals potential drug targets for aggressive tumors.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Castration-resistant prostate cancer (CRPC) presents aggressive tumors with limited treatment options following androgen receptor (AR) dependence loss.
- Understanding the molecular heterogeneity of CRPC is crucial for developing effective therapies.
Purpose of the Study:
- To molecularly classify CRPC subtypes beyond AR-dependent and neuroendocrine phenotypes.
- To identify novel therapeutic targets and guide treatment strategies for CRPC.
Main Methods:
- Utilized ATAC-seq, RNA-seq, and DNA sequencing on organoids, patient-derived xenografts, and cell lines.
- Applied transcriptomic signatures to classify a cohort of 366 CRPC patients.
Main Results:
- Identified two novel AR-negative/low subtypes: Wnt-dependent and stem cell-like (SCL).
- The SCL subtype, driven by activator protein-1 (AP-1) transcription factors, is the second most prevalent CRPC subtype.
- Discovered AP-1 interaction with YAP/TAZ and TEAD proteins maintains SCL subtype-specific chromatin accessibility and transcriptomic profiles.
Conclusions:
- A molecular classification of CRPC reveals distinct subtypes, including the SCL group.
- The findings highlight AP-1, YAP/TAZ, and TEAD as potential therapeutic targets in SCL CRPC.
- This classification can inform personalized treatment decisions for CRPC patients.
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