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Updated: Aug 5, 2026
Intra-Cardiac Injection of Human Prostate Cancer Cells to Create a Bone Metastasis Xenograft Mouse Model
Published on: November 4, 2022
An Integrated Preclinical Platform for Lethal Neuroendocrine Prostate Cancer from Rapid Autopsy Bone and Liver
Abstract:
Treatment-emergent neuroendocrine prostate cancer (NEPC) is an aggressive, therapy-resistant disease arising in up to 20% of castration resistant prostate cancers, yet robust biologically relevant preclinical models remain scarce. Here, we describe a technical blueprint for establishing an integrated platform of patient-derived models from visceral and bone metastases collected through a prostate cancer rapid autopsy program (PC RAP). We report the establishment and characterization of patient-derived xenograft (PDX) models from liver metastasis tissue, liver and bone metastasis-derived organoid lines (PDOs), and corresponding patient-derived organoid xenograft (PDOX) models. In addition, we established, to our knowledge, the first mesenchymal stem cell (MSC) cultures derived from neuroendocrine prostate cancer (NEPC) bone metastases. The PDOs preserved intratumoral heterogeneity, displaying both CRPC-NE and CRPC-adenocarcinoma features. These organoids retained neuroendocrine identity across multiple passages, with transcriptomic profiles concordant with the original patient tissue and matched PDX models generated at our institution and at the National Cancer Institute (NCI Patient-Derived Models Repository). To model the bone metastatic microenvironment, we generated novel organoid-based New Approach Methodologies (NAMs) by co-culturing PDOs with iPSC-derived bone marrow organoids, establishing a physiologically relevant vascularized organotypic model of PC bone metastasis. To extend our studies in vivo, we established preclinical models using the liver and bone metastasis-derived organoid models. The PDOX models were tumorigenic and developed spontaneous lymph node metastases, providing clinically relevant models for investigating lethal NEPC biology. Together, these complementary patient-derived models provide a robust and versatile platform for investigating NEPC biology, metastatic progression, and evaluating new therapeutic strategies.
Graphical Abstract:
Highlights: Novel preclinical models of visceral and bone metastases established from a prostate cancer rapid autopsy program.This study is the first to establish mesenchymal stem cell cultures from NEPC bone metastases.PDOs preserve heterogeneity, showing both CRPC-NE and CRPC-Adeno features, with transcriptomic profiles concordant with originator tissue and PDX models.PC RAP-derived organoids are tumorigenic in vivo and generate spontaneous lymph node metastases.
Insights
Researchers developed new preclinical models for aggressive neuroendocrine prostate cancer (NEPC) using patient samples. These models, including organoids and xenografts, accurately reflect tumor heterogeneity and aid in studying NEPC biology and treatment strategies.
Area of Science:
- Oncology
- Cancer Biology
- Preclinical Models
Background:
- Treatment-emergent neuroendocrine prostate cancer (NEPC) is an aggressive, therapy-resistant subtype of castration-resistant prostate cancer (CRPC).
- Robust, biologically relevant preclinical models for NEPC are scarce, hindering research into its biology and treatment.
- Existing models often fail to capture the heterogeneity and metastatic potential of NEPC.
Purpose of the Study:
- To establish an integrated platform of patient-derived preclinical models for neuroendocrine prostate cancer (NEPC).
- To characterize novel models including patient-derived xenografts (PDX), organoid lines (PDOs), and organoid xenografts (PDOX) from NEPC metastases.
- To develop advanced in vitro models, such as organoid-based New Approach Methodologies (NAMs), to simulate the bone metastatic microenvironment.
Main Methods:
- Established patient-derived models from liver and bone metastases via a prostate cancer rapid autopsy program (PC RAP).
- Generated PDX, PDO, and PDOX models, alongside novel mesenchymal stem cell (MSC) cultures from NEPC bone metastases.
- Developed organotypic models by co-culturing PDOs with iPSC-derived bone marrow organoids to mimic the bone metastatic niche.
Main Results:
- Successfully established diverse PDX, PDO, and PDOX models preserving intratumoral heterogeneity and neuroendocrine features.
- PDOs demonstrated transcriptomic concordance with original patient tissue and matched PDX models.
- PDOX models were tumorigenic in vivo and developed spontaneous lymph node metastases, validating their clinical relevance.
Conclusions:
- The developed platform provides a robust and versatile set of complementary patient-derived models for NEPC research.
- These models are suitable for investigating NEPC biology, metastatic progression, and evaluating novel therapeutic strategies.
- This work addresses the critical need for biologically relevant preclinical models in aggressive NEPC.
