Utilizing Patient-Derived Epithelial Ovarian Cancer Tumor Organoids to Predict Carboplatin Resistance
Abstract
:1. Introduction
2. Materials and Methods
2.1. Subjects
2.2. Tumor Organoid (TO) Development and Validation
2.3. Chemosensitivity Screens
2.4. Sequencing Methods
2.5. Gene Mutation and Gene Expression Bioinformatic Analysis
2.6. Statistical Analysis
3. Results
3.1. Subject Demographic and Treatment Charactistics
3.2. Tumor Organoid Validation
3.3. Chemosensitivity Screens
3.4. Clinical Outcomes
3.5. Tumor Organoid Mutation Analysis
3.6. Tumor Organoid Gene Expression Analysis
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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ID | Age | TNM Stage | FIGO Stage | Primary Site | Histology | Grade |
---|---|---|---|---|---|---|
UK1236 | 48 | ypT3cN0M1 | IIIC | Ovary | Serous | 3 |
UK1254 | 49 | ypT3cNX | IIIC | Ovary | Serous | 3 |
UK1267 | 55 | T2bN0 | IIB | Fallopian Tube | Serous | 3 |
UK1393 | 46 | T3cNX | IIIC | Ovary 1 | Serous | 3 |
UK2238 | 58 | T3aN1b | IIIA | Fallopian Tube | Serous | 3 |
UK2326 | 62 | T3cNX | IIIC | Ovary | Serous | 3 |
ID | Residual Disease (cm) | Neoadjuvant | Adjuvant | Maintenance |
---|---|---|---|---|
UK1236 | 0 | carboplatin and paclitaxel 1 × 1 cycle; carboplatin and abraxane × 2 cycles | carboplatin and abraxane × 3 cycles | none |
UK1254 | <0.5 | carboplatin and paclitaxel × 3 cycles | carboplatin and paclitaxel × 3 cycles | GOG 3020: rucaparib v. placebo and nivolumab v. placebo |
UK1267 | 0 | None | carboplatin and paclitaxel × 6 cycles | none |
UK1393 | 0 | None | carboplatin and paclitaxel × 6 cycles; bevacizumab with cycles 2–6 | none |
UK2238 | <0.5 | None | carboplatin and paclitaxel × 6 cycles | olaparib |
UK2326 | <0.5 | None | carboplatin and paclitaxel × 6 cycles | none |
ID | Carboplatin EC50 (µM) | PFS (Days) |
---|---|---|
UK2326 | 0.8 | 398 |
UK1267 | 1.1 | 338 |
UK2238 | 3.3 | 391 |
UK1236 | 28.5 | 579 |
UK1393 | 44.8 | 445 |
UK1254 | 50.2 1 | 252 |
A. Upregulated | |||||
Gene | LogFC | p Value | QValue (FDR) | Pathway ID | Pathway Description |
1. AQP1 | 8.722968 | 1.46 × 10−15 | 2.26 × 10−11 | GO:0022857 | Transmembrane transport activity |
2. TMEM178B | 6.489275 | 1.30 × 10−14 | 1.01 × 10−10 | --- | --- |
3. RELN | 7.083244 | 1.29 × 10−13 | 6.68 × 10−10 | GO:0030154 | Cell dedifferentiation |
4. ZNF723 | 8.998623 | 1.08 × 10−12 | 4.20 × 10−9 | GO:0003700 | DNA Binding transcription factor activity |
5. HAVCR1 | 9.870356 | 3.29 × 10−11 | 1.02 × 10−7 | GO:00023676 | Immune system process |
6. FXYD2 | 8.374937 | 8.24 × 10−10 | 2.13 × 10−6 | GO:0030234 | Enzyme regulator activity |
7. TGM3 | 6.3814 | 1.01 × 10−9 | 2.24 × 10−6 | GO:0006464 | Cellular protein modification process |
8. OGFRL1 | 3.648762 | 1.25 × 10−9 | 2.41 × 10−6 | GO:0007165 | Signal transduction |
9. LIPC | 5.511889 | 2.91 × 10−8 | 4.31 × 10−5 | GO:0006629 | Lipid metabolic process |
10. ADGRF2 | 9.051376 | 3.06 × 10−8 | 4.31 × 10−5 | GO:0007165 | Signal transduction |
B. Downregulated | |||||
Gene | LogFC | p Value | QValue (FDR) | Pathway ID | Pathway Description |
1. MAPK1 | −10.0724 | 2.43 × 10−9 | 4.19 × 10−6 | GO:0030154 | Cell differentiation |
2. ARNT2 | −9.9226 | 3.89 × 10−7 | 0.000463 | GO:0006950 | Response to stress |
3. STRA6 | −5.39401 | 6.80 × 10−6 | 0.00405 | GO:0006629 | Lipid metabolic process |
4. RBP1 | −5.05496 | 8.05 × 10−6 | 0.004168 | GO:0006629 | Lipid metabolic process |
5. ANTXR1 | −5.06802 | 1.13 × 10−5 | 0.005453 | GO:0007010 | Cytoskeleton organization |
6. LTBP1 | −4.19728 | 3.59 × 10−5 | 0.01285 | GO:0006464 | Cellular protein modification process |
7. AXIN2 | −5.6952 | 4.47 × 10−5 | 0.01442 | GO:0008283 | Cell population proliferation |
8. SLFN11 | −3.93117 | 8.66 × 10−5 | 0.02396 | GO:0006950 | Cell response to stress |
9. PHACTR1 | −5.39943 | 9.58 × 10−5 | 0.025592 | GO:0007010 | Cytoskeleton organization |
10. LYPD1 | −4.77696 | 0.000116 | 0.030426 | GO:0007267 | Cell–cell signaling |
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Gorski, J.W.; Zhang, Z.; McCorkle, J.R.; DeJohn, J.M.; Wang, C.; Miller, R.W.; Gallion, H.H.; Dietrich, C.S.; Ueland, F.R.; Kolesar, J.M. Utilizing Patient-Derived Epithelial Ovarian Cancer Tumor Organoids to Predict Carboplatin Resistance. Biomedicines 2021, 9, 1021. https://doi.org/10.3390/biomedicines9081021
Gorski JW, Zhang Z, McCorkle JR, DeJohn JM, Wang C, Miller RW, Gallion HH, Dietrich CS, Ueland FR, Kolesar JM. Utilizing Patient-Derived Epithelial Ovarian Cancer Tumor Organoids to Predict Carboplatin Resistance. Biomedicines. 2021; 9(8):1021. https://doi.org/10.3390/biomedicines9081021
Chicago/Turabian StyleGorski, Justin W., Zhuwei Zhang, J. Robert McCorkle, Jodi M. DeJohn, Chi Wang, Rachel W. Miller, Holly H. Gallion, Charles S. Dietrich, Frederick R. Ueland, and Jill M. Kolesar. 2021. "Utilizing Patient-Derived Epithelial Ovarian Cancer Tumor Organoids to Predict Carboplatin Resistance" Biomedicines 9, no. 8: 1021. https://doi.org/10.3390/biomedicines9081021