Patient-derived ovarian cancer organoid carries immune microenvironment and blood vessel keeping high response to cisplatin

Abstract

Ovarian cancer is high recurrence and mortality malignant tumor. The most common ovarian cancer was High-Grade Serous Ovarian Cancer. However, High-Grade Serous Ovarian Cancer organoid is rare, which organoid with patient immune microenvironment and blood vessels even absence. Here, we report a novel High-Grade Serous Ovarian Cancer organoid system derived from patient ovarian cancer samples. These organoids recapitulate High-Grade Serous Ovarian Cancer organoids’ histological and molecular heterogeneity while preserving the critical immune microenvironment and blood vessels, as evidenced by the presence of CD34⁺ endothelial cells. Whole exome sequencing identifies key mutations (CSMD3, TP53, GABRA6). Organoids show promise in testing cisplatin sensitivity for patients resistant to carboplatin and paclitaxel, with notable responses in cancer proteoglycans and p53 (TP53) signaling, like ACTG/ACTB1/AKT2 genes and BBC3/MDM2/PERP. Integration of immune microenvironment and blood vessels enhances potential for novel therapies like immunotherapies and angiogenesis inhibitors. Our work may provide a new detection system and theoretical basis for ovarian cancer research and individual therapy.

Keywords

cisplatin / organoid / ovarian cancer / tumor microenvironment (TME) / vascularization

References

[1] Lisio MA, Fu L, Goyeneche A, Gao ZH, Telleria C. High-Grade Serous Ovarian Cancer: basic sciences, clinical and therapeutic standpoints. Int J Mol Sci. 2019; 20(4): 952.

[2] Grabska K, Pilarska I, Magdalena Fudalej M, Deptała A, Badowska-Kozakiewicz A. What is new about ovarian malignancies? Współczesna Onkol. 2021; 25(4): 225-231.

[3] Nero C, Vizzielli G, Lorusso D, et al. Patient-derived organoids and high grade serous ovarian cancer: from disease modeling to personalized medicine. J Exp Clin Canc Res. 2021; 40(1): 116.

[4] Webb PM, Jordan SJ. Epidemiology of epithelial ovarian cancer. Best Practice & Research Clinical Obstetrics & Gynaecology. 2017; 41: 3-14.

[5] Lheureux S, Braunstein M, Oza AM. Epithelial ovarian cancer: evolution of management in the era of precision medicine. CA Cancer J Clin. 2019; 69(4): 280-304.

[6] Veneziani AC, Gonzalez-Ochoa E, Alqaisi H, et al. Heterogeneity and treatment landscape of ovarian carcinoma. Nat Rev Clin Oncol. 2023; 20(12): 820-842.

[7] Gaitskell K, Hermon C, Barnes I, et al. Ovarian cancer survival by stage, histotype, and pre-diagnostic lifestyle factors, in the prospective UK Million Women Study. Cancer Epidemiol. 2022; 76: 102074.

[8] Torre LA, Trabert B, DeSantis CE, et al. Ovarian cancer statistics, 2018. CA Cancer J Clin. 2018; 68(4): 284-296.

[9] Ledermann JA. First-line treatment of ovarian cancer: questions and controversies to address. Ther Adv Med Oncol. 2018; 10: 175883591876823.

[10] Vergote I, Denys H, Greve JD, et al. Treatment algorithm in patients with ovarian cancer. Facts Views Vis ObGyn. 2020; 12(3): 227.

[11] Chandra A, Pius C, Nabeel M, et al. Ovarian cancer: current status and strategies for improving therapeutic outcomes. Cancer Med. 2019; 8(16): 7018-7031.

[12] Falzone L, Bordonaro R, Libra M. SnapShot: cancer chemotherapy. Cell. 2023; 186(8): 1816-1816. e1

[13] Havasi A, Cainap SS, Havasi AT, Cainap C. Ovarian cancer—insights into platinum resistance and overcoming it. Medicina (Mex). 2023; 59(3): 544.

[14] Leung D, Price ZK, Lokman NA, et al. Platinum-resistance in epithelial ovarian cancer: an interplay of epithelial–mesenchymal transition interlinked with reprogrammed metabolism. J Transl Med. 2022; 20(1): 556.

[15] Konstantinopoulos PA, Matulonis UA. Clinical and translational advances in ovarian cancer therapy. Nat Cancer. 2023; 4(9): 1239-1257.

[16] Harter P, Sehouli J, Vergote I, et al. Randomized trial of cytoreductive surgery for relapsed ovarian cancer. N Engl J Med. 2021; 385(23): 2123-2131.

[17] Leary A, Tan D, Ledermann J. Immune checkpoint inhibitors in ovarian cancer: where do we stand? Ther Adv Med Oncol. 2021; 13: 175883592110398.

[18] Kotnik EN, Mullen MM, Spies NC, et al. Genetic characterization of primary and metastatic High-Grade Serous Ovarian Cancer tumors reveals distinct features associated with survival. Commun Biol. 2023; 6(1): 688.

[19] Kandalaft LE, Dangaj Laniti D, Coukos G. Immunobiology of High-Grade Serous Ovarian Cancer: lessons for clinical translation. Nat Rev Cancer. 2022; 22(11): 640-656.

[20] Voutsadakis IA. Further understanding of high-grade serous ovarian carcinogenesis: potential therapeutic targets. Cancer Manag Res. 2020; 12: 10423-10437.

[21] Sun J, Yan C, Xu D, et al. Immuno-genomic characterisation of High-Grade Serous Ovarian Cancer reveals immune evasion mechanisms and identifies an immunological subtype with a favourable prognosis and improved therapeutic efficacy. Br J Cancer. 2022; 126(11): 1570-1580.

[22] Neal JT, Li X, Zhu J, et al. Organoid modeling of the tumor immune microenvironment. Cell. 2018; 175(7): 1972-1988. doi:10.1016/j.cell.2018.11.021 e16

[23] Bose S, Clevers H, Shen X. Promises and challenges of organoid-guided precision medicine. Med. 2021; 2(9): 1011-1026.

[24] Zhou Z, Cong L, Cong X. Patient-derived organoids in precision medicine: drug screening, organoid-on-a-chip and living organoid biobank. Front Oncol. 2021; 11: 762184.

[25] Sun XY, Ju XC, Li Y, et al. Generation of vascularized brain organoids to study neurovascular interactions. eLife. 2022; 11: e76707.

[26] Mansour AA, Gonçalves JT, Bloyd CW, et al. An in vivo model of functional and vascularized human brain organoids. Nat Biotechnol. 2018; 36(5): 432-441.

[27] Seidlitz T, Stange DE. Gastrointestinal cancer organoids—applications in basic and translational cancer research. Exp Mol Med. 2021; 53(10): 1459-1470.

[28] Lo YH, Karlsson K, Kuo CJ. Applications of organoids for cancer biology and precision medicine. Nat Cancer. 2020; 1(8): 761-773.

[29] Kopper O, de Witte CJ, Lohmussaar K, et al. An organoid platform for ovarian cancer captures intra-and interpatient heterogeneity. Nat Med. 2019; 25(5): 838-849. doi:10.1038/s41591-019-0422-6

[30] Nanki Y, Chiyoda T, Hirasawa A, et al. Patient-derived ovarian cancer organoids capture the genomic profiles of primary tumours applicable for drug sensitivity and resistance testing. Sci Rep. 2020; 10(1): 12581.

[31] Senkowski W, Gall-Mas L, Falco MM, et al. A platform for efficient establishment and drug-response profiling of High-Grade Serous Ovarian Cancer organoids. Dev Cell. 2023; 58(12): 1106-1121. e7

[32] Liu HD, Xia BR, Jin MZ, Lou G. Organoid of ovarian cancer: genomic analysis and drug screening. Clin Transl Oncol. 2020; 22(8): 1240-1251.

[33] Xu J, Fang Y, Chen K, et al. Single-cell RNA sequencing reveals the tissue architecture in human High-Grade Serous Ovarian Cancer. Clin Cancer Res. 2022; 28(16): 3590-3602.

[34] Kong Q, Yan X, Cheng M, et al. p62 promotes the mitochondrial localization of p53 through its UBA domain and participates in regulating the sensitivity of ovarian cancer cells to cisplatin. Int J Mol Sci. 2022; 23(6): 3290.

[35] Tchounwou PB, Dasari S, Noubissi FK, Ray P, Kumar S. Advances in our understanding of the molecular mechanisms of action of cisplatin in cancer therapy. J Exp Pharmacol. 2021; 13: 303-328.

[36] Pectasides D, Fountzilas G, Aravantinos G, et al. Advanced stage clear-cell epithelial ovarian cancer: the Hellenic Cooperative Oncology Group experience. Gynecol Oncol. 2006; 102(2): 285-291.

[37] Kopper O, De Witte CJ, Lõhmussaar K, et al. An organoid platform for ovarian cancer captures intra-and interpatient heterogeneity. Nat Med. 2019; 25(5): 838-849. doi:10.1038/s41591-019-0422-6

[38] Cao Q, Li L, Zhao Y, et al. PARPi decreased primary ovarian cancer organoid growth through early apoptosis and base excision repair pathway. Cell Transplant. 2023; 32: 9636897231187996.

[39] Lou L, Wang K, Leng L, et al. Unveiling cell organoid: a vanguard in organoid research. Cell Organoid. 2024. doi:10.26599/CO.2024.9410000

[40] Fang Y, Akhtar H, Wang J. The application of organoids in toxicity test of environmental pollutants. Cell Organoid. 2024. doi:10.26599/CO.2024.9410002

[41] Shi Y, Liu J, Li L, et al. Patient-derived skin tumor organoids with immune cells respond to metformin. Cell Organoid. 2024. doi:10.26599/CO.2024.9410001

[42] Wang C, Huang A, Shi Y, et al. An advanced culture methodology suitable for the self-assemble and tissue-fragment derived intrahepatic cholangiocarcinoma organoids. Cell Organoid. doi:10.26599/CO.2024.9410003

[43] Zhang J, Liu J, Shi Y, et al. Generation of patient-derived glioblastoma organoids: a comparative study of enzymatic digestion and mechanical fragmentation methods. Cell Organoid. doi:10.26599/CO.2024.9410004

[44] Han X, Cai C, Deng W, et al. Landscape of human organoids: ideal model in clinics and research. Innovation (Camb). 2024; 5(3): 100620.

RIGHTS & PERMISSIONS

2024 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.