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Combining molecular characteristics and therapeutic analysis of PDOs predict clinical responses and guide PDAC
Peng Li1,2,3, Minli Huang1,2, Mengyao Li1,2
1Division of Cancer Biology, Laboratory Animal Center, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, PR China.
Background:
The emergence of targeted therapies and immunotherapy has broadened treatment options for patients with pancreatic ductal adenocarcinoma (PDAC). Despite this, traditional drug selection, predominantly relies on tumor markers and clinical staging, has underutilized these drugs due to ignoring patient genomic diversity. Patient-derived organoids (PDOs) and corresponding patient-derived organoid xenograft (PDOX) models offer a way to better understand and address this.
Methods:
In this study, we established PDOs and PDOX models from PDAC clinical samples. These models were analyzed using immunohistochemistry, H&E staining, and genomic profiling. Drug screening with 111 FDA-approved drugs was performed on PDOs, and drug responses in PDOs and PDOX models were compared to assess consistency with clinical treatment outcomes. Gene analysis was conducted to explore the molecular mechanisms underlying variations in drug responses. Additionally, by analyzing the sequencing results from various drug-sensitive groups, the identified differential gene-drug metabolism gene UGT1A10 were modulated in PDOs to evaluate its impact on drug efficacy. A co-culture system of PDOs with immune cells was developed to study the efficacy of immunotherapies.
Results:
PDOs and matched PDOX models retain the morphological, biological, and genomic characteristics of the primary tumor. Exome sequencing and RNA sequencing confirmed both the consistency and heterogeneity among the PDOs. High-throughput drug screening revealed significant variability in drug sensitivity across different organoids, yet PDOs and PDOX derived from the same patient exhibited a high degree of concordance in response to clinical chemotherapy agents. The gene expression analysis of PDOs with significant differences in drug sensitivity revealed UGT1A10 as a crucial regulator. The knockdown of UGT1A10 notably increased drug sensitivity. Furthermore, immune cells demonstrated specific cytotoxicity towards the organoids, underscoring the potential of the co-culture system for application in tumor immunotherapy.
Conclusion:
Our results highlight the necessity for personalized treatment strategies that consider genomic diversity beyond tumor markers, thus validating the utility of PDOs and PDOX models in advancing PDAC research and personalized medicine.
Insights
Patient-derived organoids (PDOs) and xenografts (PDOX) accurately model pancreatic cancer, revealing genomic diversity for personalized therapies. These models show UGT1A10 influences drug response, aiding targeted treatment development.
Area of Science:
- Oncology
- Genomics
- Translational Medicine
Background:
- Pancreatic ductal adenocarcinoma (PDAC) treatment options are expanding with targeted therapies and immunotherapy.
- Traditional drug selection often overlooks patient genomic diversity, limiting treatment efficacy.
- Patient-derived organoids (PDOs) and patient-derived organoid xenografts (PDOX) offer promising preclinical models for PDAC.
Purpose of the Study:
- To establish and characterize PDO and PDOX models from PDAC samples.
- To assess drug sensitivity and identify molecular mechanisms of response using these models.
- To evaluate the potential of PDOs in immunotherapy research.
Main Methods:
- Establishment and characterization of PDOs and PDOX models from PDAC clinical samples.
- Genomic profiling (exome and RNA sequencing), immunohistochemistry, and H&E staining.
- High-throughput drug screening of 111 FDA-approved drugs on PDOs, gene analysis, UGT1A10 modulation, and co-culture with immune cells.
Main Results:
- PDOs and PDOX models recapitulated the primary tumor's characteristics.
- Significant variability in drug sensitivity was observed across organoids, with high concordance between PDOs and PDOX from the same patient.
- UGT1A10 was identified as a key regulator of drug sensitivity, with its knockdown enhancing efficacy. Immune cell co-cultures showed potential for immunotherapy studies.
Conclusions:
- Personalized treatment strategies for PDAC must account for genomic diversity.
- PDO and PDOX models are valuable tools for advancing PDAC research and personalized medicine.
- Targeting UGT1A10 and utilizing immunotherapy models show promise for improved patient outcomes.
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