Related Experiment Video

Updated: May 24, 2025

Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
12:13

Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients

Published on: November 19, 2019

6.7K

Defined cellular reprogramming of androgen receptor-active prostate cancer to neuroendocrine prostate cancer

Shan Li1, Kai Song2, Huiyun Sun1,3

  • 1Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA.

Biorxiv : the Preprint Server for Biology
|March 3, 2025
PubMed

Insights

Researchers converted androgen receptor-positive prostate cancer (ARPC) to neuroendocrine prostate cancer (NEPC) using specific factors. This study reveals how ASCL1 and NeuroD1 silence AR signaling and drive NEPC development, offering insights into therapeutic resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Neuroendocrine prostate cancer (NEPC) often develops from androgen receptor-positive prostate cancer (ARPC) through neuroendocrine transdifferentiation (NEtD).
  • This NEtD is a resistance mechanism against therapies targeting androgen receptor (AR) signaling.
  • Models to study NEtD drivers and their impact on AR signaling are currently limited.

Purpose of the Study:

  • To develop a model system for studying NEtD in prostate cancer.
  • To identify key factors driving the conversion of ARPC to NEPC.
  • To understand the molecular mechanisms underlying AR signaling suppression and NEPC lineage establishment.

Main Methods:

  • Utilized a genetically defined cellular reprogramming strategy to convert ARPC to NEPC.
  • Employed candidate factors, including ASCL1 and NeuroD1, to induce transdifferentiation.
  • Analyzed transcriptomic and epigenomic changes during the ARPC to NEPC lineage conversion process.
  • Investigated the role of RE-1 silencing transcription factor (REST) in NEPC development.

Main Results:

  • Successfully converted ARPC to AR-independent NEPC using specific candidate factors.
  • Delineated critical roles for pioneer factors ASCL1 and NeuroD1 in silencing AR expression and signaling.
  • Demonstrated that ASCL1 and NeuroD1 remodel chromatin at AR regulatory elements.
  • Elucidated dynamic transcriptomic and epigenomic landscapes during acute lineage conversion.
  • Distinguished the roles of ASCL1/NeuroD1 from REST inactivation in NEPC lineage establishment and MHC I modulation.

Conclusions:

  • ASCL1 and NeuroD1 are key drivers of NEtD in prostate cancer, acting by silencing AR signaling through chromatin remodeling.
  • The study provides a novel model for investigating NEtD and its associated therapeutic resistance.
  • Findings offer crucial insights into the biological mechanisms of NEPC development and potential therapeutic targets.
Keywords:
ASCL1NeuroD1androgen receptorcellular reprogramminglineage plasticityneuroendocrine prostate cancerneuroendocrine transdifferentiation

More Related Videos

A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer07:25

A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer

Published on: March 6, 2018

13.0K
A Rapid Filter Insert-based 3D Culture System for Primary Prostate Cell Differentiation09:23

A Rapid Filter Insert-based 3D Culture System for Primary Prostate Cell Differentiation

Published on: February 13, 2017

8.5K

Related Concept Videos

Introduction to Nuclear Reprogramming01:14

Introduction to Nuclear Reprogramming

Nuclear reprogramming is the process of switching gene expression of one cell type to that of another cell type, usually from a differentiated cell state to an undifferentiated cell state. Differentiation occurs during processes such as development and morphogenesis, tissue regeneration, and malignancy. Cells can also be artificially induced to reprogram their gene expression by techniques such as nuclear transfer, induced pluripotency, and cell fusion. Such techniques have many applications in...
1.9K
Somatic to iPS Cell Reprogramming01:29

Somatic to iPS Cell Reprogramming

Reprogramming alters the gene expression in somatic cells, transforming them into induced pluripotent stem (iPS) cells over several generations. Scientists can reprogram cells by introducing genes for four transcription factors—Oct4, Sox2, Klf4, and c-Myc (OSKM) by viral or non-viral methods. These factors are also known as Yamanaka factors after Shinya Yamanaka, who first generated iPS cells using mouse skin cells. Yamanaka was awarded the Nobel Prize in Physiology or Medicine in 2012...
2.2K
Methods of Nuclear Reprogramming01:24

Methods of Nuclear Reprogramming

Nuclear reprogramming is a process of transforming one cell type into an unrelated cell type by epigenetic changes that alter the cell’s original gene expression pattern. Such epigenetic changes force cells to express a different set of genes, which play a significant role in inducing transformation into other cell types. Nuclear reprogramming offers applications in reproductive cloning for livestock propagation and regenerative medicine — developing patient-specific cells for...
1.8K