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Updated: Oct 16, 2025
Prostate Organoid Cultures as Tools to Translate Genotypes and Mutational Profiles to Pharmacological Responses
Published on: October 24, 2019
Extracellular Matrix in Synthetic Hydrogel-Based Prostate Cancer Organoids Regulate Therapeutic Response to EZH2 and
Matthew J Mosquera1, Sungwoong Kim2,3, Rohan Bareja4,5
1Sibley School of Mechanical Engineering, Cornell University, Ithaca, NY, 14850, USA.
Abstract:
Following treatment with androgen receptor (AR) pathway inhibitors, ≈20% of prostate cancer patients progress by shedding their AR-dependence. These tumors undergo epigenetic reprogramming turning castration-resistant prostate cancer adenocarcinoma (CRPC-Adeno) into neuroendocrine prostate cancer (CRPC-NEPC). No targeted therapies are available for CRPC-NEPCs, and there are minimal organoid models to discover new therapeutic targets against these aggressive tumors. Here, using a combination of patient tumor proteomics, RNA sequencing, spatial-omics, and a synthetic hydrogel-based organoid, putative extracellular matrix (ECM) cues that regulate the phenotypic, transcriptomic, and epigenetic underpinnings of CRPC-NEPCs are defined. Short-term culture in tumor-expressed ECM differentially regulated DNA methylation and mobilized genes in CRPC-NEPCs. The ECM type distinctly regulates the response to small-molecule inhibitors of epigenetic targets and Dopamine Receptor D2 (DRD2), the latter being an understudied target in neuroendocrine tumors. In vivo patient-derived xenograft in immunocompromised mice showed strong anti-tumor response when treated with a DRD2 inhibitor. Finally, we demonstrate that therapeutic response in CRPC-NEPCs under drug-resistant ECM conditions can be overcome by first cellular reprogramming with epigenetic inhibitors, followed by DRD2 treatment. The synthetic organoids suggest the regulatory role of ECM in therapeutic response to targeted therapies in CRPC-NEPCs and enable the discovery of therapies to overcome resistance.
Insights
Neuroendocrine prostate cancer (CRPC-NEPC) arises from castration-resistant prostate cancer (CRPC) and lacks targeted therapies. This study defines extracellular matrix (ECM) cues regulating CRPC-NEPC and identifies DRD2 inhibition as a therapeutic strategy, even in resistant conditions.
Area of Science:
- Oncology
- Cancer Biology
- Epigenetics
Background:
- Androgen receptor (AR) pathway inhibitors lead to AR-dependence loss in ~20% of prostate cancers.
- Tumors epigenetically reprogram from castration-resistant prostate cancer adenocarcinoma (CRPC-Adeno) to neuroendocrine prostate cancer (CRPC-NEPC).
- CRPC-NEPCs lack targeted therapies and effective organoid models for therapeutic target discovery.
Purpose of the Study:
- To define extracellular matrix (ECM) cues regulating CRPC-NEPC phenotypes, transcriptomics, and epigenetics.
- To explore ECM's role in therapeutic response to epigenetic inhibitors and Dopamine Receptor D2 (DRD2) targeting.
- To develop and utilize a synthetic organoid model for CRPC-NEPC research.
Main Methods:
- Integrated analysis of patient tumor proteomics, RNA sequencing, and spatial-omics.
- Development of a synthetic hydrogel-based organoid model using tumor-expressed ECM.
- In vivo patient-derived xenograft (PDX) models in immunocompromised mice.
- Assessment of small-molecule inhibitors targeting epigenetic regulators and DRD2.
Main Results:
- Culture in tumor-expressed ECM altered DNA methylation and gene expression in CRPC-NEPCs.
- ECM type differentially modulated responses to epigenetic inhibitors and DRD2.
- DRD2 inhibition showed significant anti-tumor activity in vivo.
- Combination therapy (epigenetic inhibitors followed by DRD2) overcame drug-resistant ECM-mediated resistance.
Conclusions:
- ECM plays a critical regulatory role in CRPC-NEPC therapeutic response.
- DRD2 is a promising therapeutic target for CRPC-NEPC, particularly in resistant contexts.
- Synthetic organoids are valuable tools for discovering therapies against CRPC-NEPC and overcoming treatment resistance.
