Patient Derived Organoids (PDOs), Extracellular Matrix (ECM), Tumor Microenvironment (TME) and Drug Screening: State of the Art and Clinical Implications of Ovarian Cancer Organoids in the Era of Precision Medicine
Abstract
:Simple Summary
Abstract
1. Introduction
2. Patient-Derived Organoids (PDOs)
3. Extracellular Matrix (ECM) and Tumor Microenvironment (TME)
4. Drug Screening
5. Clinical Implications and Future Prospective
5.1. Patient Derived Organoids (PDOs)
5.2. Tumor Microenvironment (TME) and Extracellular Matrix (ECM)
5.3. Drug Screening
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Site of Origin | Histological Types | Number of Patients | Number of Organoids | Success Rate | Genomic Characterization | Concordance Rate | |
---|---|---|---|---|---|---|---|
Pauli 2017 [30] | Ovaries | Serous | 1 | 1 | 100% | WES | 86% concordance between organoids and native tumor tissues (based on the analysis of 1062 specific cancer genes). |
Jabs 2017 [31] | Ovaries Ascites Pleural effusion | HGSC | 9 | 9 (8 + 1) | 100% | WGS | n.s |
Hill 2018 [32] | Ovaries Omentum Pleural effusion Mesentery Diaphragm | HGSC LGSC | 22 | 33 | 80–90% | WES | 98.8% of mutations were identified both in the tumors and in the matched organoid line. |
Phan 2019 [33] | Ovaries Peritoneum | Peritoneal HGSC Carcinosarcoma | 4 | 4 | 100% | Not performed | n.s |
Kopper 2019 [35] | Ovaries Peritoneum Diaphragm Rectum Lymph nodes Ascites Pleural effusion | EC BOT HGSC LGSC MC CCC | 32 | 56 | 65% | WGS | High in S-SNVs and CNVs. |
Maru 2019 [36] | n.s | EC Brenner tumors HGSC MC CCC | 15 | 9 | 90% | 409 gene panel | High |
Hoffman 2020 [37] | Peritoneum Omentum | HGSC | 13 | 15 | 30% | 121 gene panel | High |
Sun 2020 [38] | n.s | Serous | 10 | 10 | n.s | RNA-seq | n.s |
Maenhoudt 2020 [40] | Ovaries Omentum Rectum | HGSC LGSC CCC MC MT | 27 | 12 | 44% | WGS | 98% of the genetic alterations (S-CNAs) similarly present in both primary tumor and resultant organoid line. |
Nanki 2020 [34] | Ovaries | HGSC CCC EC BOT non-serous OC | 35 | 28 | 80% | 1053-gene panel | Median concordance 59.1% (36.1–73.1%) of the genomic variants were shared among organoids and primary tumours |
de Witte 2020 [41] | Ascites Omentum Adnexa Peritoneum Lymph nodes Uterus | HGSC EC LGSC CCC BOT MC | 23 | 36 | n.s | WGS | 67% of single-nucleotide variants, comparable copy-number states |
Chen 2020 [42] | Ascites Pleural effusion | HGSC Peritoneal HGSC | 6 | 14 | n.s | RNA-seq | n.s |
Gorski 2021 [43] | n.s | HGSC | 6 | 6 | 100% | DNA-seq RNA-seq | High |
Tao 2022 [44] | Primary tumor and metastatic lesions | HGSC EC CC BOT | n.s | 7 | 85% | WES | 91.5% of SNVs and SVs present in the original tumor were maintained in the derived organoids. |
Wan 2021 [45] | n.s | HGSC | 13 | 12 | 92% | RNA-seq | n.s |
Wang 2022 [39] | n.s | HGSC | n.s | n.s | n.s | RNA-seq | n.s |
Wan 2022 [46] | Ovaries | BOT | 13 | 10 | 77% | RNA-seq | High |
Extracellular Matrix | Culturing Medium | Organoid Formation (Days) | |
---|---|---|---|
Pauli 2017 [30] | Matrigel | Glutamax, B27 (Gibco), 100 U/mL penicillin, 100 μg/mL streptomycin, Primocin 100 μg/mL, N-Acetylcysteine 1.25 mM, Mouse Recombinant EGF 50 ng/mL, Recombinant Human FGF-basic 1 ng/mL, Y-27632 10 μM, A-83-01 500 nM, SB202190 10 μM, Nicotinamide 10 mM, PGE2 1 μM, Noggin 50 mL, R-Spondin 25 mL | n.s |
Jabs 2017 [31] | 2% Matrigel | 50 lg/mL gentamicin, 0.5 lg/mL Fungizone, lM ROCK inhibitor Y27632, 5% CO2 | Up to 10 days |
Hill 2018 [32] | Matrigel | Advanced DMEM/F12, 1% penicillin streptomycin, Glutamax, 1% HEPES, 100 ng/mL R-spondin 1, 100 ng/mL Noggin, 50 ng/mL EGF, 10 ng/mL FGF-10, 10 ng/mL FGF2-1× B27, 10 mM Nicotinamide, 1.25 mM N-acetylcysteine, 1 μM Prostaglandin E2, 10 μM SB202190, 500 nm A83–01-Y-27632 | 7–14 days |
Phan 2019 [33] | Matrigel or Cultrex BME | PrEGM medium or Mammocult | n.s |
Kopper 2019 [35] | Cultrex BME | 25% conditioned human RSPO1 medium, 12 mM HEPES, 1% Glutamax, 2% B27, 10 ng mL−1 human EGF, 100 ng mL−1 human noggin, 100 ng mL−1 human FGF10, 1% N2 10 mM nicotinamide, 9 μM ROCK inhibitor, 0.5 μM, TGF, βR Kinase Inhibitor IV, hydrocortison, forskolin, heregulinβ-1 | 3–14 days |
Maru 2019 [36] | Matrigel | DMEM/F12 (Thermo Fisher Scientific, Watham, MA, USA), 50 ng/mL human EGF (Peprotech, Rocky Hill, NJ, USA), 250 ng/mL R-spondin1 (R&D, Minneapolis, MN, USA), 100 ng/mL Noggin (Peprotech), 10 μM Y27632 (Wako, Osaka, Japan), 1 μM Jagged-1 (AnaSpec, Fremont, CA, USA), L-glutamine solution (Wako), penicillin/streptomycin (Sigma-Aldrich, St. Louis, MO, USA), amphotericin B suspension (Wako) | n.s |
Hoffman 2020 [37] | Matrigel | Wnt3a (mouse 25%), R-Spondin 1 (mouse 25%), FGF 10, human 100 ng·mL−1, Noggin, human 100 ng·mL−1, EGF, human 10 ng·mL−1,Y-27632 9 µM, SB431542 0.5 µM, B27 supplement 1x, N2 supplement 1x, Nicotinamide 1 mM, GlutaMax 100x 1x Hepes 10 mM, Penicillin/Streptomycin 100 U·mL−1/100 mg·mL−1, Advanced DMEM/F12 1x | n.s |
Sun 2020 [38] | Matrigel | n.s | n.s |
Maenhoudt 2020 [40] | Matrigel | DMEM/F12 (Thermo Fisher Scientific), 10% fetal bovine serum (FBS; Thermo Fisher Scientific), 2% Penicillin/streptomycin, 10% dimethyl sulfoxide, 1–5 mM Nicotinamide, 1.25 mM N-acetylcysteine, 10 nM 17-β Estradiol, 10−1 μM p38i (SB203580), 2 ng/mL bFGF (OCOM 1-2), 50 ng/mL NRG1 (OCOM4), 10 ng/mL FGF10 (OCOM1-2), 50 ng/mL RSPO1 (rec or CM), 20 ng/mL IGF1 (OCOM3-4) | n.s |
Nanki 2020 [34] | Matrigel | Advanced DMEM/F12, 2mMHEPES, 1 × GlutaMAX-I, 1X B27 supplement 10 nM Leu15-Gastrin, 1 mM N-acetylcystein, 100 ng/mL recombinant human IGF-1, 50 ng/mL recombinant human FGF-2, 20% Afamin/Wnt3a CM, 1 μg/mL humanR-spondin, 100 ng/mL Noggin, 500 nM A-83-01, 200 U/mL penicillin/ streptomycin 10 μM Y-27632 | 7–21 days |
de Witte 2020 [41] | Matrigel | 1% GlutaMAX, 2%B27, 1%N2, 10 ng mL−1 human EGF, 100 ng mL−1 human noggin, 100 ng mL−1 human FGF10, 1 mM nicotinamide, 9 μM ROCK inhibitor, 0.5 μMTGF-βR Kinase Inhibitor IV, Hydrocortisone, Forskolin, heregulinβ-1 | 20 days |
Chen 2020 [42] | Cultrex Reduced Growth Factor Basement Membrane Extract, Type 2 (BME) | DMEM/ F12, 10% R-spondin1 2% B27 Supplement, 10 mM HEPES, 1% Glutamax, 1.25 mM N-acetyl cysteine, 100 μg/mL Primocin, 1% Antibiotic-Antimycotic, 1 mM nicotinamide, 0.5 μM A 83–01, 5 nM Neuregulin 1, 5 ng/mL FGF-7, 20 ng/mL FGF-10, 100 ng/mL Noggin, 5 ng/mL EGF-0.5 μM, SB 202190 5 μM, Y-27632 | 3–4 days |
Gorski 2021 [43] | Matrigel | n.s | n.s |
Tao 2022 [44] | Matrigel | Oded Kopper’s Protocol, Advanced DMEM/F12, 1x Glutamax, 10 mM HEPES, Noggin, Rspo1, N-Acetylcysteine (500 mM), Primocin, A83-01 (5 mM), Fgf10 (100 μg/mL), Heregulinβ-1 (75 μg/mL), Y27632 (100 mM), EGF (500 μg/mL), Forskolin (10 mM), Hydrocortisone (250 μg/mL), β-Estradiol (100 μM) | n.s |
Wan 2021 [45] | 15% Matrigel | DMEM/10% FBS, 1% Pen/Strep, 30 ng/mL of IL-2 | n.s |
Wang 2022 [39] | Matrigel | DMEM, 1% penicillin-streptomycin, 10 mmol/L nicotinamide | 7 days |
Wan 2022 [46] | 70% Matrigel | Oded Kopper’s Protocol, Advanced DMEM/F12, 1x Glutamax, 10 mM HEPES, Noggin, Rspo1, N-Acetylcysteine (500 mM), Primocin, A83-01 (5 mM), Fgf10 (100 μg/mL), Heregulinβ-1 (75 μg/mL), Y27632 (100 mM), EGF (500 μg/mL), Forskolin (10 mM), Hydrocortisone (250 μg/mL), β-Estradiol (100 μM) | n.s |
Traditional Anticancer Drugs | PARPi/ICI | Others (Action Mechanism) | |
---|---|---|---|
Pauli 2017 [30] | Not performed | ||
Jabs 2017 [31] | Carboplatin, Paclitaxel, Doxorubicin | Olaparib | MK5108 (Aurora A kinase inhibitor), NSC23766 (inhibitor of Rac1 activation), Cyclopamine (inhibitor of the Hh pathway), AZD2014 (inhibitor of mTORC1 and mTORC2), AZD5363 (Akt inhibitor), BKM120 (PI3Ki), Decitabine, Azacytidine, Belinostat (HDACi), Dasatinib (TKI) |
Hill 2018 [32] | Carboplatin | Olaparib | Prexasertib (CHK1 inhibitor), VE-822 (ATR inhibitor) |
Phan 2019 [33] | 240 protein kinase inhibitor compounds FDA-approved or in clinical development at two various concentrations | ||
Kopper 2019 [35] | Carboplatin, Paclitaxel, Gemcitabine | Niraparib | Alpelisib, Pictilisib, MK2206, AZD8055 (PI3K/AKT/mTOR pathway inhibitors), Adavosertib (Wee1 inhibitors) |
Maru 2019 [36] | Paclitaxel, Cisplatin | ||
Hoffman 2020 [37] | Carboplatin | ||
Sun 2020 [38] | Cisplatin | ||
Maenhoudt 2020 [40] | Paclitaxel, Doxorubicin, Carboplatin, Gemcitabine | Nutlin-3 (MDM2 inhibitors) | |
Nanki 2020 [34] | Cisplatin, Carboplatin, Paclitaxel, Docetaxel, Vinorelbine, Doxorubicin, Gemcitabine, Tamoxifen, Trabectedin | Olaparib | Vorinostat (HDACi), Belinostat (HDACi), Cediranib (VEGFi), Pazopanib (VEGFi), Topotecan, Eribulin, SN-38, Etoposide |
de Witte 2020 [41] | Carboplatin, Paclitaxel, Gemcitabine | Olaparib Niraparib Rucaparib | Afatinib (EGFR inhibitor), Vemurafenib (B-Raf Inhibitor), Flavopiridol (CDK inhibitor), Adavosertib (Wee1 Inhibitors), Alpelisib (PISKi), AZD8055 (PISKi), Pictilisib (PISKi), Cobimetinib (MEKi) |
Chen 2020 [42] | Carboplatin, Taxol | Mocetinostat 8 (HDAC inhibitor), Trametinib (MEK inhibitor), LY294002 (PI3k inhibitor), AZD5363 (Akt Inhibitor), BBI503 (NANOG/CD133 Inhibitor), MK-1775 (Wee-1 Inhibitor), APR-246 (p53 reactivator), CB5083 (ATPase inhibitor), Napabucasin, (STAT3 Inhibitor), Sorafenib (VEGFi) | |
Gorski 2021 [43] | Carboplatin | ||
Tao 2022 [44] | Cisplatin, Paclitaxel, Gemcitabine | Niraparib Olaparib | AZD7762 (Chk1 inhibitor), SAHA (HDACi), deguelin, SN-38 (topoisomerase I inhibitor), |
Wan 2021 [45] | bispecific anti-PD-1/PD-L1 ICB antibodies to monospecific anti-PD-1 and anti-PD-L1 molecules | ||
Wang 2022 [39] | Not performed | ||
Wan 2022 [46] | Bractoppin (BRCA inhibitor) |
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Spagnol, G.; Sensi, F.; De Tommasi, O.; Marchetti, M.; Bonaldo, G.; Xhindoli, L.; Noventa, M.; Agostini, M.; Tozzi, R.; Saccardi, C. Patient Derived Organoids (PDOs), Extracellular Matrix (ECM), Tumor Microenvironment (TME) and Drug Screening: State of the Art and Clinical Implications of Ovarian Cancer Organoids in the Era of Precision Medicine. Cancers 2023, 15, 2059. https://doi.org/10.3390/cancers15072059
Spagnol G, Sensi F, De Tommasi O, Marchetti M, Bonaldo G, Xhindoli L, Noventa M, Agostini M, Tozzi R, Saccardi C. Patient Derived Organoids (PDOs), Extracellular Matrix (ECM), Tumor Microenvironment (TME) and Drug Screening: State of the Art and Clinical Implications of Ovarian Cancer Organoids in the Era of Precision Medicine. Cancers. 2023; 15(7):2059. https://doi.org/10.3390/cancers15072059
Chicago/Turabian StyleSpagnol, Giulia, Francesca Sensi, Orazio De Tommasi, Matteo Marchetti, Giulio Bonaldo, Livia Xhindoli, Marco Noventa, Marco Agostini, Roberto Tozzi, and Carlo Saccardi. 2023. "Patient Derived Organoids (PDOs), Extracellular Matrix (ECM), Tumor Microenvironment (TME) and Drug Screening: State of the Art and Clinical Implications of Ovarian Cancer Organoids in the Era of Precision Medicine" Cancers 15, no. 7: 2059. https://doi.org/10.3390/cancers15072059