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2025 Ruth Porat and Anthony Paduano – PCF Young Investigator Award

MBD4-Driven AR Reprogramming and Luminal Lineage Specification in Prostate Cancer

Xuanrong Chen, PhD
Weill Cornell Medicine 

Mentors: Chris Barbieri; Andrea Sboner

Description:

  • Prostate cancer initiation and progression involve reprogramming androgen receptor (AR) signaling from normal growth-suppressive functions to tumor-driving functions. How this switch in AR function occurs remains unclear. There is an urgent need for therapies that selectively suppress AR oncogenic activity while preserving its normal functions.
  • Dr. Chen previously identified MBD4 as a key regulator of AR-driven transcription and prostate luminal lineage specification. MBD4 loss shifts AR function from maintaining normal prostate cell programs to driving oncogenic pathways, resulting in a more aggressive prostate cancer phenotype. Dr. Chen hypothesizes that MBD4 acts as a molecular switch, modulating AR transcriptional programs by preserving normal prostate lineage maintenance in prostate cancer.
  • In this project, Dr. Chen will apply functional genomics with advanced organoid systems to define the role of MBD4 in AR oncogenic reprogramming, elucidate the role of MBD4 in prostate luminal lineage specification, and characterize how MBD4 downregulation drives the transition to prostate cancer over time.
  • If successful, this project will establish the mechanisms by which MBD4 loss drives oncogenic AR function and disrupts prostate luminal lineage specification. Additionally, this research will highlight novel therapeutic vulnerabilities and provide a foundation for targeted strategies to restore normal, non-oncogenic AR activity, ultimately aiming to prevent disease progression and improve clinical outcomes for patients with advanced prostate cancer. 

What this means to patients: The androgen receptor (AR) is ordinarily involved in maintaining normal prostate cell behavior, but in cancer its functions change, and it becomes the primary driver of tumor cell growth. Dr. Chen has identified a regulator of AR, MBD4, as key to this transition from normal to oncogenic AR functions. This project will define the mechanisms by which loss of MBD4 promotes oncogenic AR function and explore its potential as a therapeutic target, which could lead to new treatment strategies for patients with prostate cancer.