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Establishing 3D organoid models from patient-derived conditionally reprogrammed cells to bridge preclinical and clinical insights in pancreatic cancer.
Literature Information
| DOI | 10.1186/s12943-025-02374-y |
|---|---|
| PMID | 40462147 |
| Journal | Molecular cancer |
| Impact Factor | 33.9 |
| JCR Quartile | Q1 |
| Publication Year | 2025 |
| Times Cited | 1 |
| Keywords | 3D organoid culture, Conditionally reprogrammed cell (CRC) organoids, Drug sensitivity screening, FOLFIRINOX, Gemcitabine plus nab-paclitaxel (Abraxane) |
| Literature Type | Journal Article |
| ISSN | 1476-4598 |
| Pages | 162 |
| Issue | 24(1) |
| Authors | Jin Su Kim, Chan Hee Park, Eunyoung Kim, Hee Seung Lee, Jinyoung Lee, Jeehoon Kim, Eun Hee Kam, Sanghee Nam, Moon Jae Chung, Jeong Youp Park, Seung Woo Park, Sangwoo Kim, Galam Leem, Seungmin Bang |
TL;DR
This study establishes a Matrigel-based three-dimensional (3D) organoid culture model from patient-derived conditionally reprogrammed cell lines, demonstrating that these organoids preserve the molecular characteristics of pancreatic tumors and better reflect clinical drug responses compared to traditional two-dimensional (2D) cultures. The findings highlight the potential of 3D organoid models in advancing precision medicine and identifying predictive biomarkers for more effective treatment strategies in pancreatic cancer.
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3D organoid culture · Conditionally reprogrammed cell (CRC) organoids · Drug sensitivity screening · FOLFIRINOX · Gemcitabine plus nab-paclitaxel (Abraxane)
Abstract
BACKGROUND Pancreatic cancer is a highly lethal malignancy with limited treatment response. Despite advancements in treatment, systemic chemotherapy remains the primary therapeutic approach for over 80% of patients, with no established biomarkers to guide drug selection. Traditional two-dimensional (2D) culture models fail to replicate the tumor microenvironment, necessitating the development of more advanced models, such as three-dimensional (3D) organoid models.
METHODS We established 3D organoid cultures using patient-derived conditionally reprogrammed cell (CRC) lines, originally cultured under 2D conditions. These CRC organoids were developed using a Matrigel-based platform without organoid-specific medium components to preserve the intrinsic molecular subtypes of the cells. Morphological, molecular, and drug sensitivity analyses were performed to compare the clinical responses of 3D CRC organoids with those of their 2D counterparts and clinical responses.
RESULTS The 3D CRC organoids retained the molecular characteristics, transcriptomic and mutational profiles of the parental tumors and displayed distinct morphologies corresponding to cancer stages and differentiation. Drug response profiling of gemcitabine plus nab-paclitaxel (Abraxane) and FOLFIRINOX demonstrated that the 3D organoids more accurately mirrored patient clinical responses than the 2D cultures. Notably, the IC50 values for the 3D organoids were generally higher, reflecting the structural complexity and drug penetration barriers observed in vivo.
CONCLUSION Matrigel-based 3D organoid culture models provide a robust platform for pre-clinical drug evaluation, overcoming the limitations of 2D models. Although time- and resource-intensive, integrating both 2D and 3D platforms enables efficient initial screening and validation. This approach holds promise for identifying predictive biomarkers and advancing precision medicine in pancreatic cancer treatment.
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Primary Questions Addressed
- What specific advantages do 3D organoid models offer over traditional 2D cultures in studying pancreatic cancer?
- How do the molecular characteristics of 3D organoids compare to those of patient tumors in terms of treatment response?
- What are the potential challenges in scaling up the production of 3D organoid models for broader clinical applications?
- In what ways can the findings from 3D organoid drug response profiling inform personalized treatment strategies for pancreatic cancer patients?
- How might the integration of 3D organoid models with other experimental approaches enhance our understanding of pancreatic cancer biology?
Key Findings
Background and Objective
Pancreatic cancer is one of the most lethal malignancies, characterized by poor treatment responses and limited therapeutic options. Despite advancements in treatment strategies, systemic chemotherapy remains the mainstay for over 80% of patients, with a notable absence of established biomarkers for guiding drug selection. Traditional two-dimensional (2D) culture models are inadequate in mimicking the tumor microenvironment, highlighting the need for more sophisticated models, such as three-dimensional (3D) organoid cultures.
Main Methods/Materials/Experimental Design
The study focused on developing 3D organoid cultures from patient-derived conditionally reprogrammed cell (CRC) lines that were initially cultured in 2D. The organoids were established using a Matrigel-based platform without specific organoid medium components to maintain the intrinsic molecular subtypes of the cells.
Experimental Workflow
Key Results and Findings
- The 3D CRC organoids successfully retained the molecular characteristics, transcriptomic, and mutational profiles of the original tumors.
- Distinct morphologies of the organoids were observed, corresponding to various cancer stages and differentiation levels.
- Drug response profiling indicated that the 3D organoids provided a more accurate reflection of patient clinical responses compared to 2D cultures.
- Notably, the IC50 values for the 3D organoids were generally higher, suggesting that the structural complexity and drug penetration barriers present in vivo were better represented.
Main Conclusions/Significance/Innovation
The study concluded that Matrigel-based 3D organoid culture models serve as a robust platform for pre-clinical drug evaluation, effectively addressing the limitations associated with 2D models. While the 3D model is more time- and resource-intensive, its integration with 2D platforms allows for efficient initial screening and validation of drug responses. This innovative approach holds significant promise for identifying predictive biomarkers and enhancing precision medicine in the treatment of pancreatic cancer.
Research Limitations and Future Directions
| Limitations | Future Directions |
|---|---|
| Time- and resource-intensive model | Explore more efficient culture methods |
| Potential variability in organoid response | Investigate standardization of organoid production |
| Limited patient sample diversity | Expand studies to include diverse patient demographics |
Future research should focus on optimizing the 3D culture conditions, exploring the use of alternative scaffolding materials, and validating the predictive capabilities of the organoids in larger, more diverse patient cohorts.
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Literatures Citing This Work
- Cell and tissue reprogramming: Unlocking a new era in medical drug discovery. - Chandan K Sen;Andrew J Friday;Sashwati Roy - Pharmacological reviews (2025)
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