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Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
Published on: November 22, 2021
Differences in chemotherapeutic drug sensitivity before and after patient-derived tumor organoid construction
Fang Shao1, Xin Huang2, Zhihong Ma3
1Laboratory of Oncology, The Second People's Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, China; Largescale Equipment Platform, Changzhou Medical Center, The Second People's Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, China.
Background:
Patient-derived organoids (PDOs) have emerged as promising preclinical models for various tumor types. This study aimed to optimize the process of constructing 3D organoid models and facilitate the development of personalized therapies for gastric and colon cancers.
Methods:
Tumor tissues were divided into two parts: one part was dissociated into a single-cell suspension, and the other part was used to culture tumor organoids. RNA sequencing (RNA-seq) was performed on both tumor cells and cultured organoids. Four chemotherapeutic agents-Oxaliplatin (L-OHP), Gemcitabine (GEM), 5-Fluorouracil (5-FU), and Paclitaxel (PTX)-were utilized to assess cytotoxicity and proliferation in both organoids and freshly isolated tumor cells, then the effects of these agents were evaluated.
Results:
Organoids were successfully established from both surgically resected and biopsy-derived tumor tissues. Phenotypic analysis indicated that the organoids retained the histological features and expression profiles of the original tumors. Notably, the morphological characteristics of the organoids remained stable across passages, demonstrating robust growth over time. Differentially expressed genes were identified in both gastric and colon cancer PDOs. GO and KEGG pathway analyses revealed similar gene enrichment in gastric and colon PDOs. Both gastric and colon cancer PDOs exhibited increased significant sensitivity to PTX and 5-FU compared to freshly isolated cancer cells. Furthermore, the expression of most stemness-related genes was reduced after organoid culture.
Conclusions:
We successfully established organoid models that demonstrated robust growth and heightened drug sensitivity compared to freshly isolated tumor cells. These findings suggest that caution should be exercised when interpreting drug sensitivity results from organoid-based assays.
Insights
Patient-derived organoids (PDOs) offer a promising model for cancer research. This study optimized PDOs for gastric and colon cancers, showing enhanced drug sensitivity compared to fresh tumor cells.
Area of Science:
- Oncology
- Cancer Research
- 3D Cell Culture
Background:
- Patient-derived organoids (PDOs) are emerging as valuable preclinical models for diverse cancer types.
- This research focused on optimizing the construction of 3D organoid models for personalized gastric and colon cancer therapies.
Purpose of the Study:
- To optimize the generation of patient-derived organoids (PDOs) from gastric and colon tumors.
- To evaluate the drug sensitivity of PDOs compared to freshly isolated tumor cells.
- To facilitate the development of personalized therapeutic strategies for gastrointestinal cancers.
Main Methods:
- Tumor tissues were dissociated for single-cell suspension or cultured as organoids.
- RNA sequencing (RNA-seq) was performed on both tumor cells and organoids.
- Cytotoxicity and proliferation assays were conducted using Oxaliplatin, Gemcitabine, 5-Fluorouracil, and Paclitaxel.
Main Results:
- Successful establishment of organoids from both surgical and biopsy samples.
- Organoids maintained histological features and gene expression profiles of original tumors, with stable morphology across passages.
- Gastric and colon cancer PDOs showed increased sensitivity to Paclitaxel and 5-Fluorouracil compared to fresh tumor cells; stemness gene expression decreased post-culture.
Conclusions:
- Optimized PDO models demonstrate robust growth and enhanced drug sensitivity compared to freshly isolated tumor cells.
- Findings highlight the potential of PDOs for personalized cancer therapy research.
- Caution is advised when interpreting drug sensitivity results from organoid-based assays due to observed differences.
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