Development of patient‑derived tumor organoids and a drug testing model for renal cell carcinoma

Kazama,Akira; Anraku,Tsutomu; Kuroki,Hiroo; Shirono,Yuko; Murata,Masaki; Bilim,Vladimir; Ugolkov,Andrey; Saito,Kazuhide; Tomita,Yoshihiko

doi:10.3892/or.2021.8177

Development of patient‑derived tumor organoids and a drug testing model for renal cell carcinoma

Authors:
- Akira Kazama
- Tsutomu Anraku
- Hiroo Kuroki
- Yuko Shirono
- Masaki Murata
- Vladimir Bilim
- Andrey Ugolkov
- Kazuhide Saito
- Yoshihiko Tomita
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Affiliations: Department of Urology, Division of Molecular Oncology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951‑8510, Japan, Actuate Therapeutics, Inc., Fort Worth, TX 76107, USA
Published online on: September 1, 2021 https://doi.org/10.3892/or.2021.8177
Article Number: 226
Copyright: © Kazama et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The selection of effective therapeutic agents is critical for improving the survival of patients with renal cell carcinoma (RCC). The aim of the present study was to develop an ex vivo drug testing assay using patient‑derived tumor organoid (TO) cultures. For this purpose, surgical tumor specimens were obtained from 20 patients with RCC. TOs were developed ex vivo from freshly resected RCC tumors, and their histopathological and molecular characteristics were evaluated using histological staining and whole‑exome sequencing (WES). Using a cell viability assay, the therapeutic efficacy of standard of care tyrosine kinase inhibitors in RCC TOs was determined. It was found that TOs recapitulated the histological features of primary RCC tumors. Using WES, a strong concordance was identified at the genetic level between the primary tumors and their corresponding TOs. Using patient‑derived TO models, a prototype of an ex vivo drug testing assay was developed, and it was found that RCC TOs exhibited differential responses to sunitinib, pazopanib, cabozantinib, axitinib and sorafenib treatment. On the whole, although the predictive value of the current assay has to be tested and validated in future clinical studies, the findings of the present study demonstrate a novel approach for ex vivo drug testing in patient‑derived TO models, which may have potential for use in the personalized treatment of cancer patients.

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1	Kabaria R, Klaassen Z and Terris MK: Renal cell carcinoma: Links and risks. Int J Nephrol Renovasc Dis. 9:45–52. 2016.PubMed/NCBI
2	Escudier B, Porta C, Schmidinger M, Rioux-Leclercq N, Bex A, Khoo V, Grünwald V, Gillessen S and Horwich A; ESMO Guidelines Committee. Electronic address, : clinicalguidelines@esmo.org: Renal cell carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 30:706–720. 2019. View Article : Google Scholar : PubMed/NCBI
3	Malone ER, Oliva M, Sabatini PJ, Stockley TL and Siu LL: Molecular profiling for precision cancer therapies. Genome Med. 12:82020. View Article : Google Scholar : PubMed/NCBI
4	Fatehullah A, Tan SH and Barker N: Organoids as an in vitro model of human development and disease. Nat Cell Biol. 18:246–254. 2016. View Article : Google Scholar : PubMed/NCBI
5	Clevers H: Modeling development and disease with organoids. Cell. 165:1586–1597. 2016. View Article : Google Scholar : PubMed/NCBI
6	Rookmaaker MB, Schutgens F, Verhaar MC and Clevers H: Development and application of human adult stem or progenitor cell organoids. Nat Rev Nephrol. 11:546–554. 2015. View Article : Google Scholar : PubMed/NCBI
7	Kapałczyńska M, Kolenda T, Przybyła W, Zajączkowska M, Teresiak A, Filas V, Ibbs M, Bliźniak R, Łuczewski Ł and Lamperska K: 2D and 3D cell cultures-a comparison of different types of cancer cell cultures. Arch Med Sci. 4:910–919. 2018.PubMed/NCBI
8	Broutier L, Mastrogiovanni G, Verstegen MM, Francies HE, Gavarró LM, Bradshaw CR, Allen GE, Arnes-Benito R, Sidorova O, Gaspersz MP, et al: Human primary liver cancer-derived organoid cultures for disease modeling and drug screening. Nat Med. 12:1424–1435. 2017. View Article : Google Scholar : PubMed/NCBI
9	Gao D, Vela I, Sboner A, Iaquinta PJ, Karthaus WR, Gopalan A, Dowling C, Wanjala JN, Undvall EA, Arora VK, et al: Organoid cultures derived from patients with advanced prostate cancer. Cell. 159:176–187. 2014. View Article : Google Scholar : PubMed/NCBI
10	Ganesh K, Wu C, O'Rourke KP, Szeglin BC, Zheng Y, Sauvé CG, Adileh M, Wasserman I, Marco MR, Kim AS, et al: A rectal cancer organoid platform to study individual responses to chemoradiation. Nat Med. 25:1607–1614. 2019. View Article : Google Scholar : PubMed/NCBI
11	Romero-Calvo I, Weber CR, Ray M, Brown M, Kirby K, Nandi RK, Long TM, Sparrow SM, Ugolkov A, Qiang W, et al: Human organoids share structural and genetic features with primary pancreatic adenocarcinoma tumors. Mol Cancer Res. 17:70–83. 2019. View Article : Google Scholar : PubMed/NCBI
12	Saito Y, Muramatsu T, Kanai Y, Ojima H, Sukeda A, Hiraoka N, Arai E, Sugiyama Y, Matsuzaki J, Uchida R, et al: Establishment of patient-derived organoids and drug screening for biliary tract carcinoma. Cell Rep. 27:1265–1276.e4. 2019. View Article : Google Scholar : PubMed/NCBI
13	Lee SH, Hu W, Matulay JT, Silva MV, Owczarek TB, Kim K, Chua CW, Barlow LJ, Kandoth C, Williams AB, et al: Tumor evolution and drug response in patient-derived organoid models of bladder cancer. Cell. 173:515–528.e17. 2018. View Article : Google Scholar : PubMed/NCBI
14	Bilim V, Yuuki K, Itoi T, Muto A, Kato T, Nagaoka A, Motoyama T and Tomita Y: Double inhibition of XIAP and Bcl-2 axis is beneficial for retrieving sensitivity of renal cell cancer to apoptosis. Br J Cancer. 98:941–949. 2008. View Article : Google Scholar : PubMed/NCBI
15	Liston DR and Davis M: Clinically relevant concentrations of anticancer drugs: A guide for nonclinical studies. Clin Cancer Res. 23:3489–3498. 2017. View Article : Google Scholar : PubMed/NCBI
16	Kim M, Mun H, Sung CO, Cho EJ, Jeon HJ, Chun SM, Jung DJ, Shin TH, Jeong GS, Kim DK, et al: Patient-derived lung cancer organoids as in vitro cancer models for therapeutic screening. Nat Commun. 10:39912019. View Article : Google Scholar : PubMed/NCBI
17	Aberle MR, Burkhart RA, Tiriac H, Olde Damink SW, Dejong CH, Tuveson DA and van Dam RM: Patient-derived organoid models help define personalized management of gastrointestinal cancer. Br J Surg. 105:e48–e60. 2018. View Article : Google Scholar : PubMed/NCBI
18	van de Wetering M, Francies HE, Francis JM, Bounova G, Iorio F, Pronk A, van Houdt W, van Gorp J, Taylor-Weiner A, Kester L, et al: Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell. 161:933–945. 2015. View Article : Google Scholar : PubMed/NCBI
19	Grassi L, Alfonsi R, Francescangeli F, Signore M, De Angelis ML, Addario A, Costantini M, Flex E, Ciolfi A, Pizzi S, et al: Organoids as a new model for improving regenerative medicine and cancer personalized therapy in renal diseases. Cell Death Dis. 10:2012019. View Article : Google Scholar : PubMed/NCBI
20	Neal JT, Li X, Zhu J, Giangarra V, Grzeskowiak CL, Ju J, Liu IH, Chiou SH, Salahudeen AA, Smith AR, et al: Organoid modeling of the tumor immune microenvironment. Cell. 175:1972–1988.e16. 2018. View Article : Google Scholar : PubMed/NCBI
21	Vlachogiannis G, Hedayat S, Vatsiou A, Jamin Y, Fernández-Mateos J, Khan K, Lampis A, Eason K, Huntingford I, Burke R, et al: Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science. 359:920–926. 2018. View Article : Google Scholar : PubMed/NCBI
22	Bian S, Repic M, Guo Z, Kavirayani A, Burkard T, Bagley JA, Krauditsch C and Knoblich JA: Author correction: Genetically engineered cerebral organoids model brain tumor formation. Nat Methods. 15:7482018. View Article : Google Scholar : PubMed/NCBI
23	Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, Venugopal B, Kollmannsberger C, Negrier S, Uemura M, et al: Avelumab plus Axitinib versus Sunitinib for advanced renal-cell carcinoma. N Engl J Med. 380:1103–1115. 2019. View Article : Google Scholar : PubMed/NCBI
24	Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, Pouliot F, Alekseev B, Soulières D, Melichar B, et al: KEYNOTE-426 investigators. Pembrolizumab plus Axitinib versus Sunitinib for advanced renal-cell carcinoma. N Engl J Med. 380:1116–1127. 2019. View Article : Google Scholar : PubMed/NCBI
25	Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, Plimack ER, Barthélémy P, Porta C, George S, et al: CheckMate 214 investigators. Nivolumab plus Ipilimumab versus Sunitinib in advanced renal-cell carcinoma. N Engl J Med. 378:1277–1290. 2018. View Article : Google Scholar : PubMed/NCBI
26	Zerdes I, Tolia M, Tsoukalas N, Mitsis M, Kardamakis D, Pistevou-Gombaki K, Tsekeris P and Kyrgias G: Systemic therapy of metastatic renal cell carcinoma: Review of the current literature. Urologia. 86:3–8. 2019. View Article : Google Scholar : PubMed/NCBI
27	Liu C, Qin T, Huang Y, Li Y, Chen G and Sun C: Drug screening model meets cancer organoid technology. Transl Oncol. 13:1008402020. View Article : Google Scholar : PubMed/NCBI
28	Li M and Izpisua Belmonte JC: Organoids-preclinical models of human disease. N Engl J Med. 380:569–579. 2019. View Article : Google Scholar : PubMed/NCBI
29	Bleijs M, van de Wetering M, Clevers H and Drost J: Xenograft and organoid model systems in cancer research. EMBO J. 38:e1016542019. View Article : Google Scholar : PubMed/NCBI
30	Drost J and Clevers H: Organoids in cancer research. Nat Rev Cancer. 18:407–418. 2018. View Article : Google Scholar : PubMed/NCBI