A modular patient-derived organoid–xenograft platform reveals molecular and clinical trajectories of prostate cancer progression
This study demonstrates that organoid-xenograft models can effectively mimic prostate cancer progression and identify potential biomarkers for aggressive subtypes.
Where it sits
this study against the rest of the goserelin corpusSummary and findings
The study developed a modular patient-derived organoid-xenograft platform to model prostate cancer progression. It used two advanced prostate cancer PDO lines to create xenografts, maintaining key characteristics of the original tumors. The research identified a rare cell population enriched upon androgen deprivation, linked to aggressive prostate cancer subtypes.
Abstract
Patient-derived organoids (PDOs) are becoming increasingly important in prostate cancer (PCa) translational research. However, direct proof-of-concept studies demonstrating their ability to model disease evolution, identify relevant biomarkers, and accurately predict treatment response in PCa patients, remain scarce. Here, we report the establishment of serially transplantable xenografts series derived from two advanced PCa PDO lines, which can be further re-cultured as organoids. Newly-generated model series maintain key phenotypic, genomic, and functional characteristics of the original patient tumors, and emulate relevant molecular subtypes of advanced PCa. Single-cell RNA sequencing (scRNA-seq) analysis uncovers transcriptomic differences between xenograft and organoid models, as well as signaling pathways which are largely preserved and can be targeted ex vivo. Functional drug profiles correlate with molecular and clinical attributes, as exemplified by response to androgen receptor (AR) pathway inhibitors and glucocorticoid-mediated AR signaling activation. Longitudinal scRNA-seq analysis of perturbed PDOs identifies a rare PROX1 + /ALDH1A1 + cell population, which pre-exist in the treatment-naïve setting and is significantly enriched upon androgen deprivation. Notably, this cell population is similarly enriched in post-treatment samples of the original patient and is associated with aggressive AR-negative PCa molecular subtypes, suggesting a potential link with PCa progression. Our study provides proof-of-concept evidence that organoids can mirror PCa patient-specific drug sensitivity profiles and molecular paths of disease progression, uncovering pertinent biomarkers. Ultimately, our organoid-xenograft model series provide a modular and scalable platform that can readily be used for mechanistic and translational studies.
Background
Prostate cancer remains a significant clinical challenge, with progression and treatment resistance being major concerns. Patient-derived organoids (PDOs) offer a promising approach to model disease evolution and treatment response. This study aims to establish a platform using PDOs and xenografts to explore molecular trajectories and identify biomarkers in prostate cancer.
Methods
The study developed a series of xenografts from two advanced prostate cancer PDO lines. These xenografts were serially transplantable and could be re-cultured as organoids. Single-cell RNA sequencing (scRNA-seq) was used to analyze transcriptomic differences and signaling pathways. The study also examined drug response profiles and identified cell populations enriched upon treatment.
Results
The xenografts maintained key phenotypic, genomic, and functional characteristics of the original patient tumors. scRNA-seq analysis revealed transcriptomic differences between xenograft and organoid models. A rare PROX1+/ALDH1A1+ cell population was identified, which was enriched upon androgen deprivation and linked to aggressive AR-negative prostate cancer subtypes.
Interpretation
The study provides proof-of-concept that organoid-xenograft models can reflect patient-specific drug sensitivity and molecular progression in prostate cancer. While the findings are promising, they are preclinical and based on specific PDO lines, limiting their generalizability. Further validation in human trials is necessary to confirm clinical relevance.
Key findings
- Two advanced PCa PDO lines used to establish xenografts.
- Xenografts maintain phenotypic, genomic, and functional characteristics of original tumors.
- scRNA-seq analysis reveals transcriptomic differences between xenograft and organoid models.
- Rare PROX1+/ALDH1A1+ cell population enriched upon androgen deprivation.
- Cell population associated with aggressive AR-negative PCa subtypes.
Limitations
- Preclinical study using organoid and xenograft models.
- Findings limited to specific PDO lines.
- Potential lack of generalizability to all prostate cancer cases.
- No direct human trial validation.