References

biob

Биобезопасность и Биотехнология

Biosafety and Biotechnology

2707-72412957-5702

Научно-исследовательский институт проблем биологической безопасности

10.58318/2957-5702-2025-23-50-84

biob-203

Research Article

СТАТЬИ

Articles

КЛЕТОЧНЫЕ БИОТЕХНОЛОГИИ В МОДЕЛИРОВАНИИ КАНЦЕРОГЕНЕЗА И ИХ ПОТЕНЦИАЛ В ПРЕЦИЗИОННОЙ МЕДИЦИНЕ

CELLULAR BIOTECHNOLOGIES IN THE MODELING OF CARCINOGENESIS AND THEIR POTENTIAL IN PRECISION MEDICINE

Наханов

А. К.

Nakhanov

A. K.

Гвардейский

Guardeyskiy

Коканов

С. К.

Kokanov

S. K.

Гвардейский

Guardeyskiy

s.kokanov@biosafety.kz

Теребай

А. А.

Terebay

A. A.

Гвардейский

Guardeyskiy

Мараховская

Л. Г.

Marakhovskaya

L. G.

Гвардейский

Guardeyskiy

ТОО «Научно-исследовательский институт проблем биологической безопасности», Национальный холдинг «QazBioPharm»КазахстанLLP «Research Institute for Biological Safety Problems», National holding «QazBioPharm»Kazakhstan

2025

12022026

123

№23 (2025)

5084

2026

Наханов А.К., Коканов С.К., Теребай А.А., Мараховская Л.Г.

Nakhanov A.K., Kokanov S.K., Terebay A.A., Marakhovskaya L.G.

Данная работа распространяется под лицензией Creative Commons Attribution 4.0.

This work is licensed under a Creative Commons Attribution 4.0 License.

https://journal.biosafety.kz/jour/article/view/203

Онкологические заболевания являются одной из самых актуальных проблем человечества. К сожалению, современные методы профилактики и лечения рака не поспевают за тенденцией увеличения смертности и появления новых случаев данных заболеваний. Одной из причин этого является отсутствие доклинических моделей in vitro, которые бы точно имитировали человеческие опухоли, их разнообразную морфологию, молекулярные характеристики и микроокружение. Исследования опухолей, их морфологические характеристики, прогноз лечения, терапевтические подходы до сих пор проводятся на двухмерных моделях культур клеток и животных. Однако двухмерные модели культур клеток имеют ограничения из-за отсутствия тканеспецифической архитектуры, биохимических сигналов и взаимодействия между клетками и окружающей матрицей, поэтому они не могут точно отображать и моделировать сложные процессы in vivo. В свою очередь использование животных для моделирования опухолевых заболеваний и тестирования на них лекарственных препаратов не только дорогостоящее и трудоемкое занятие, но также данные модели не могут имитировать биологические реакции людей из-за видовых различий. Трехмерные модели ткани более подходящие в плане морфологии, миграции, пролиферации, реакции на лекарственное лечение, а также экспрессии генов и белков, более точно имитируют рост тканей in vivo. В данном обзоре приведены современные научные данные по использованию клеточных биотехнологий для изучения канцерогенеза и их потенциал в прецизионной медицине.

Oncological diseases are one of the most pressing problems of mankind. Unfortunately, modern methods of cancer prevention and treatment have not kept pace with the trend of increasing mortality and the emergence of new cases of these diseases. One of the reasons for this is the lack of preclinical in vitro models that would accurately simulate human tumors, their diverse morphology, molecular characteristics and microenvironment. Studies of tumors, their morphological characteristics, treatment prognosis, and therapeutic approaches are still carried out on two-dimensional models of cell and animal cultures. However, two-dimensional cell culture models have limitations due to the lack of tissue-specific architecture, biochemical signals, and interactions between cells and the surrounding matrix, so they cannot accurately display and simulate complex processes in vivo. In turn, using animals to model tumor diseases and test drugs for them is not only expensive and time-consuming, but also these models cannot simulate biological reactions of humans due to species differences. Three-dimensional tissue models are more suitable in terms of morphology, migration, proliferation, response to drug treatment, as well as gene and protein expression, and more accurately mimic tissue growth in vivo. This review presents current scientific data on the use of cellular biotechnologies to study carcinogenesis and their potential in precision medicine.

культура клетокорганоидыонкологияin vitro - моделиканцерогенезпрецизионная медицина

cell cultureorganoidsoncologyin vitro modelscarcinogenesisprecision medicine

References1

Всемирная организация здравоохранения. Global cancer burden growing – amidst mounting need for services [Электронный ресурс]. – URL: https://www.who.int/ru/news/item/01-02-2024-globalcancer-burden-growing--amidst-mounting-need-for-services (дата обращения: 06.02.2026).

Wang C., Tang Z., Zhao Y., Yao R., Li L., Sun W. Three-dimensional in vitro cancer models: a short review // Biofabrication. – 2014. – V. 6, №2. – P. 022001.

Vargo-Gogola T., Rosen J.M. Modelling breast cancer: one size does not fit all // Nat Rev Cancer. – 2007. – V. 7, №9. – P. 659-672.

Breitenbach M., Hoffmann J. Cancer models // Front Oncol. – 2018. – V. 8. – P. 401.

Schachtschneider K.M., Schwind R.M., Newson J., et al. The oncopig cancer model: an innovative large animal translational oncology platform // Front Oncol. – 2017. – V. 7. – P. 190.

Sato T., Vries R.G., Snippert H.J., van de Wetering M., Barker N., Stange D.E., van Es J.H., Abo A., Kujala P., Peters P.J., et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche // Nature. – 2009. – V. 459. – P. 262-265. – DOI: 10.1038/nature07935.

Kim K.A., Kakitani M., Zhao J., Oshima T., Tang T., Binnerts M., Liu Y., et al. Mitogenic influence of human R-spondin1 on the intestinal epithelium // Science. – 2005. – V. 309. – P. 1256-1259. – DOI: 10.1126/science.1112521.

Korinek V., Barker N., Moerer P., van Donselaar E., Huls G., Peters P.J., Clevers H. Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4 // Nat Genet. – 1998. – V. 19. – P. 379-383. – DOI: 10.1038/1270.

Sato T., van Es J.H., Snippert H.J., Stange D.E., Vries R.G., van den Born M., Barker N., Shroyer N.F., van de Wetering M., Clevers H. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts // Nature. – 2011. – V. 469. – P. 415-418. – DOI: 10.1038/nature09637.

Sasaki T., Giltay R., Talts U., Timpl R., Talts J.F. Expression and distribution of laminin alpha1 and alpha2 chains in embryonic and adult mouse tissues: an immunochemical approach // Exp Cell Res. – 2002. – V. 275. – P. 185-199. – DOI: 10.1006/excr.2002.5499.

Ootani A., Li X., Sangiorgi E., Ho Q.T., Ueno H., Toda S., Sugihara H., Fujimoto K., Weissman I.L., Capecchi M.R., et al. Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell niche // Nat Med. – 2009. – V. 15. – P. 701-706. – DOI: 10.1038/nm.1951.

Kim E., Choi S., Kang B., Kong J., Kim Y., Yoon W.H., Lee H.R., Kim S., Kim H.M., Lee H., et al. Creation of bladder assembloids mimicking tissue regeneration and cancer // Nature. – 2020. – V. 588. – P. 664-669. – DOI: 10.1038/s41586-020-3034-x.

Lee S.H., Hu W., Matulay J.T., Silva M.V., Owczarek T.B., Kim K., Chua C.W., Barlow L.J., Kandoth C., Williams A.B., et al. Tumor evolution and drug response in patient-derived organoid models of bladder cancer // Cell. – 2018. – V. 173. – P. 515-528.e17. – DOI: 10.1016/j.cell.2018.03.017.

Mullenders J., de Jongh E., Brousali A., Roosen M., Blom J.P.A., Begthel H., Korving J., Jonges T., Kranenburg O.W., Meijer R., et al. Mouse and human urothelial cancer organoids: A tool for bladder cancer research // Proc Natl Acad Sci USA. – 2019. – V. 116. – P. 4567-4574. – DOI: 10.1073/pnas.1803595116.

Abdullah K.G., Bird C.E., Buehler J.D., Gattie L.C., Savani M.R., Sternisha A.C., Xiao Y., Levitt M.M., Hicks W.H., Li W., et al. Establishment of patient-derived organoid models of lower-grade glioma // Neuro Oncol. – 2022. – V. 24. – P. 612-623. – DOI: 10.1093/neuonc/noab273.

Sachs N., de Ligt J., Kopper O., Gogola E., Bounova G., Weeber F., Balgobind A.V., Wind K., Gracanin A., Begthel H., et al. A living biobank of breast cancer organoids captures disease heterogeneity // Cell. – 2018. – V. 172. – P. 373-386. – DOI: 10.1016/j.cell.2017.11.010.

Lõhmussaar K., Oka R., Espejo Valle-Inclan J., Smits M.H.H., Wardak H., Korving J., Begthel H., Proost N., van de Ven M., Kranenburg O.W., et al. Patient-derived organoids model cervical tissue dynamics and viral oncogenesis in cervical cancer // Cell Stem Cell. – 2021. – V. 28. – P. 1380-1396. – DOI: 10.1016/j.stem.2021.03.012.

Boretto M., Maenhoudt N., Luo X., Hennes A., Boeckx B., Bui B., Heremans R., Perneel L., Kobayashi H., Van Zundert I., et al. Patient-derived organoids from endometrial disease capture clinical heterogeneity and are amenable to drug screening // Nat Cell Biol. – 2019. – V. 21. – P. 1041-1051. – DOI: 10.1038/s41556-019-0360-z.

Li X., Francies H.E., Secrier M., Perner J., Miremadi A., Galeano-Dalmau N., Barendt W.J., Letchford L., Leyden G.M., Goffin E.K., et al. Organoid cultures recapitulate esophageal adenocarcinoma heterogeneity providing a model for clonality studies and precision therapeutics // Nat Commun. – 2018. – V. 9. – P. 2983. – DOI: 10.1038/s41467-018-05190-9.

Tanaka N., Osman A.A., Takahashi Y., Lindemann A., Patel A.A., Zhao M., Takahashi H., Myers J.N. Head and neck cancer organoids established by modification of the CTOS method can be used to predict in vivo drug sensitivity // Oral Oncol. – 2018. – V. 87. – P. 49-57. – DOI: 10.1016/j.oraloncology.2018.10.018.

Driehuis E., Kolders S., Spelier S., Lõhmussaar K., Willems S.M., Devriese L.A., de Bree R., de Ruiter E.J., Korving J., Begthel H., et al. Oral mucosal organoids as a potential platform for personalized cancer therapy // Cancer Discov. – 2019. – V. 9. – P. 852-871. – DOI: 10.1158/2159-8290.CD-181522.

Van de Wetering M., Francies H.E., Francis J.M., 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. – 2015. – V. 161. – P. 933-945. – DOI: 10.1016/j.cell.2015.03.053.

Weeber F., van de Wetering M., Hoogstraat M., Dijkstra K.K., Krijgsman O., Kuilman T., Gadellaa-van Hooijdonk C.G., van der Velden D.L., Peeper D.S., Cuppen E.P., et al. Preserved genetic diversity in organoids cultured from biopsies of human colorectal cancer metastases // Proc Natl Acad Sci USA. – 2015. – V. 112. – P. 13308-13311. – DOI: 10.1073/pnas.1516689112.

Fujii M., Shimokawa M., Date S., Takano A., Matano M., Nanki K., Ohta Y., Toshimitsu K., Nakazato Y., Kawasaki K., et al. A colorectal tumor organoid library demonstrates progressive loss of niche factor requirements during tumorigenesis // Cell Stem Cell. – 2016. – V. 18. – P. 827-838. – DOI: 10.1016/j.stem.2016.04.003.

Schütte M., Risch T., Abdavi-Azar N., Boehnke K., Schumacher D., Keil M., Yildiriman R., Jandrasits C., Borodina T., Amstislavskiy V., et al. Molecular dissection of colorectal cancer in pre-clinical models identifies biomarkers predicting sensitivity to EGFR inhibitors // Nat Commun. – 2017. – V. 8. – P. 14262. – DOI: 10.1038/ncomms14262.

Ganesh K., Wu C., O'Rourke K.P., Szeglin B.C., Zheng Y., Sauvé C.G., Adileh M., Wasserman I., Marco M.R., Kim A.S., et al. A rectal cancer organoid platform to study individual responses to chemoradiation // Nat Med. – 2019. – V. 25. – P. 1607-1614. – DOI: 10.1038/s41591-019-0584-2.

Yan H.H.N., Siu H.C., Ho S.L., Yue S.S.K., Gao Y., Tsui W.Y., Chan D., Chan A.S., Wong J.W.H., Man A.H.Y., et al. Organoid cultures of early-onset colorectal cancers reveal distinct and rare genetic profiles // Gut. – 2020. – V. 69. – P. 2165-2179. – DOI: 10.1136/gutjnl-2019-320019.

Yao Y., Xu X., Yang L., Zhu J., Wan J., Shen L., Xia F., Fu G., Deng Y., Pan M., et al. Patient-derived organoids predict chemoradiation responses of locally advanced rectal cancer // Cell Stem Cell. – 2020. – V. 26. – P. 17-26.e6. – DOI: 10.1016/j.stem.2019.10.010.

Herpers B., Eppink B., James M.I., Cortina C., Cañellas-Socias A., Boj S.F., HernandoMomblona X., Glodzik D., Roovers R.C., van de Wetering M., et al. Functional patient-derived organoid screenings identify MCLA-158 as a therapeutic EGFR x LGR5 bispecific antibody with efficacy in epithelial tumors // Nat Cancer. – 2022. – V. 3. – P. 418-436. – DOI: 10.1038/s43018-022-00359-0.

Calandrini C., Schutgens F., Oka R., Margaritis T., Candelli T., Mathijsen L., Ammerlaan C., van Ineveld R.L., Derakhshan S., de Haan S., et al. An organoid biobank for childhood kidney cancers that captures disease and tissue heterogeneity // Nat Commun. – 2020. – V. 11. – P. 1310. – DOI: 10.1038/s41467-020-15155-6.

Broutier L., Mastrogiovanni G., Verstegen M.M., Francies H.E., Gavarró L.M., Bradshaw C.R., Allen G.E., Arnes-Benito R., Sidorova O., Gaspersz M.P., et al. Human primary liver cancer-derived organoid cultures for disease modeling and drug screening // Nat Med. – 2017. – V. 23. – P. 1424-1435. – DOI: 10.1038/nm.4438.

Nuciforo S., Fofana I., Matter M.S., Blumer T., Calabrese D., Boldanova T., Piscuoglio S., Wieland S., Ringnalda F., Schwank G., et al. Organoid models of human liver cancers derived from tumor needle biopsies // Cell Rep. – 2018. – V. 24. – P. 1363-1376. – DOI: 10.1016/j.celrep.2018.07.001.

Van Tienderen G.S., Li L., Broutier L., Saito Y., Inacio P., Huch M., Selaru F.M., van der Laan L.J.W., Verstegen M.M.A. Hepatobiliary tumor organoids for personalized medicine: a multicenter view on establishment, limitations, and future directions // Cancer Cell. – 2022. – V. 40. – P. 226-230. – DOI: 10.1016/j.ccell.2022.02.001.

Sachs N., Papaspyropoulos A., Zomer-van Ommen D.D., Heo I., Böttinger L., Klay D., Weeber F., Huelsz-Prince G., Iakobachvili N., Amatngalim G.D., et al. Long-term expanding human airway organoids for disease modeling // EMBO J. – 2019. – V. 38. – P. e100300. – DOI: 10.15252/embj.2018100300.

Ding R.B., Chen P., Rajendran B.K., Lyu X., Wang H., Bao J., Zeng J., Hao W., Sun H., Wong A.H., et al. Molecular landscape and subtype-specific therapeutic response of nasopharyngeal carcinoma revealed by integrative pharmacogenomics // Nat Commun. – 2021. – V. 12. – P. 3046. – DOI: 10.1038/s41467-021-23379-3.

Kawasaki K., Toshimitsu K., Matano M., Fujita M., Fujii M., Togasaki K., Ebisudani T., Shimokawa M., Takano A., Takahashi S., et al. An organoid biobank of neuroendocrine neoplasms enables genotype-phenotype mapping // Cell. – 2020. – V. 183. – P. 1420-1435.e21. – DOI: 10.1016/j.cell.2020.10.023.

Kopper O., de Witte C.J., Lõhmussaar K., Valle-Inclan J.E., Hami N., Kester L., Balgobind A.V., Korving J., Proost N., Begthel H., et al. An organoid platform for ovarian cancer captures intra- and interpatient heterogeneity // Nat Med. – 2019. – V. 25. – P. 838-849. – DOI: 10.1038/s41591-019-0422-6.

Tiriac H., Belleau P., Engle D.D., Plenker D., Deschênes A., Somerville T.D.D., Froeling F.E.M., Burkhart R.A., Denroche R.E., Jang G.H., et al. Organoid profiling identifies common responders to chemotherapy in pancreatic cancer // Cancer Discov. – 2018. – V. 8. – P. 1112-1129. – DOI: 10.1158/2159-8290.CD-18-0349.

Seino T., Kawasaki S., Shimokawa M., Tamagawa H., Toshimitsu K., Fujii M., Ohta Y., Matano M., Nanki K., Kawasaki K., et al. Human pancreatic tumor organoids reveal loss of stem cell niche factor dependence during disease progression // Cell Stem Cell. – 2018. – V. 22. – P. 454-467. – DOI: 10.1016/j.stem.2017.12.009.

Boj S.F., Hwang C.I., Baker L.A., Chio I.I., Engle D.D., Corbo V., Jager M., Ponz-Sarvise M., Tiriac H., Spector M.S., et al. Organoid models of human and mouse ductal pancreatic cancer // Cell. – 2015. – V. 160. – P. 324-338. – DOI: 10.1016/j.cell.2014.12.021.

Driehuis E., van Hoeck A., Moore K., Kolders S., Francies H.E., Gulersonmez M.C., Stigter E.C.A., Burgering B., Geurts V., Gracanin A., et al. Pancreatic cancer organoids recapitulate disease and allow personalized drug screening // Proc Natl Acad Sci USA. – 2019. – V. 116. – P. 26580-26590. – DOI: 10.1073/pnas.1911273116.

Gao D., Vela I., Sboner A., Iaquinta P.J., Karthaus W.R., Gopalan A., Dowling C., Wanjala J.N., Undvall E.A., Arora V.K., et al. Organoid cultures derived from patients with advanced prostate cancer // Cell. – 2014. – V. 159. – P. 176-187. – DOI: 10.1016/j.cell.2014.08.016.

Mout L., van Dessel L.F., Kraan J., de Jong A.C., Neves R.P.L., Erkens-Schulze S., Beaufort C.M., Sieuwerts A.M., van Riet J., Woo T.L.C., et al. Generating human prostate cancer organoids from leukapheresis enriched circulating tumour cells // Eur J Cancer. – 2021. – V. 150. – P. 179-189. – DOI: 10.1016/j.ejca.2021.03.023.

Wang B., Gan J., Liu Z., Hui Z., Wei J., Gu X., Mu Y., Zang G. An organoid library of salivary gland tumors reveals subtype-specific characteristics and biomarkers // J Exp Clin Cancer Res. – 2022. – V. 41. – P. 350. – DOI: 10.1186/s13046-022-02561-5.

Nanki K., Toshimitsu K., Takano A., Fujii M., Shimokawa M., Ohta Y., Matano M., Seino T., Nishikori S., Ishikawa K., et al. Divergent routes toward Wnt and R-spondin niche independency during human gastric carcinogenesis // Cell. – 2018. – V. 174. – P. 856-869. – DOI: 10.1016/j.cell.2018.07.027.

Tong Y., Cheng P.S.W., Or C.S., Yue S.S.K., Siu H.C., Ho S.L., Law S.Y.K., Tsui W.Y., Chan D., Ma S., et al. Escape from cell-cell and cell-matrix adhesion dependence underscores disease progression in gastric cancer organoid models // Gut. – 2023. – V. 72. – P. 242-255. – DOI: 10.1136/gutjnl-2022327121.

Yan H.H.N., Siu H.C., Law S., Ho S.L., Yue S.S.K., Tsui W.Y., Chan D., Chan A.S., Ma S., Lam K.O., et al. A comprehensive human gastric cancer organoid biobank captures tumor subtype heterogeneity and enables therapeutic screening // Cell Stem Cell. – 2018. – V. 23. – P. 882-897. – DOI: 10.1016/j.stem.2018.09.016.

Seidlitz T., Merker S.R., Rothe A., Zakrzewski F., von Neubeck C., Grützmann K., Sommer U., Schweitzer C., Schölch S., Uhlemann H., et al. Human gastric cancer modelling using organoids // Gut. – 2019. – V. 68. – P. 207-217. – DOI: 10.1136/gutjnl-2017-314549.

Togasaki K., Sugimoto S., Ohta Y., Nanki K., Matano M., Takahashi S., Fujii M., Kanai T., Sato T. Wnt signaling shapes the histologic variation in diffuse gastric cancer // Gastroenterology. – 2021. – V. 160. – P. 823-830. – DOI: 10.1053/j.gastro.2020.10.047.

Bartfeld S., Bayram T., van de Wetering M., Huch M., Begthel H., Kujala P., Vries R., Peters P.J., Clevers H. In vitro expansion of human gastric epithelial stem cells and their responses to bacterial infection // Gastroenterology. – 2015. – V. 148. – P. 126-136. – DOI: 10.1053/j.gastro.2014.09.042.

Hill S.J., Decker B., Roberts E.A., Horowitz N.S., Muto M.G., Worley M.J. Jr., Feltmate C.M., Nucci M.R., Swisher E.M., Nguyen H., et al. Prediction of DNA repair inhibitor response in short-term patient-derived ovarian cancer organoids // Cancer Discov. – 2018. – V. 8. – P. 1404-1421. – DOI: 10.1158/2159-8290.CD-18-0474.

Huang L., Holtzinger A., Jagan I., BeGora M., Lohse I., Ngai N., Nostro C., Wang R., Muthuswamy L.B., Crawford H.C., et al. Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell- and patient-derived tumor organoids // Nat Med. – 2015. – V. 21. – P. 1364-1371. – DOI: 10.1038/nm.3973.

Maier C.F., Zhu L., Nanduri L.K., Kühn D., Kochall S., Thepkaysone M.L., William D., Grützmann K., Klink B., Betge J., et al. Patient-derived organoids of cholangiocarcinoma // Int J Mol Sci. – 2021. – V. 22. – P. 8675. – DOI: 10.3390/ijms22168675.

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. – 2019. – V. 27. – P. 1265-1276. – DOI: 10.1016/j.celrep.2019.03.088.

Sato T., Stange D.E., Ferrante M., Vries R.G., Van Es J.H., Van den Brink S., Van Houdt W.J., Pronk A., Van Gorp J., Siersema P.D., et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium // Gastroenterology. – 2011. – V. 141. – P. 17621772. – DOI: 10.1053/j.gastro.2011.07.050.

Yan H.H.N., Lai J.C.W., Ho S.L., Leung W.K., Law W.L., Lee J.F.Y., Chan A.K.W., Tsui W.Y., Chan A.S.Y., Lee B.C.H., et al. RNF43 germline and somatic mutation in serrated neoplasia pathway and its association with BRAF mutation // Gut. – 2017. – V. 66. – P. 1645-1656. – DOI: 10.1136/gutjnl-2016-311849.

Chumduri C., Gurumurthy R.K., Berger H., Dietrich O., Kumar N., Koster S., Brinkmann V., Hoffmann K., Drabkina M., Arampatzi P., et al. Opposing Wnt signals regulate cervical squamocolumnar homeostasis and emergence of metaplasia // Nat Cell Biol. – 2021. – V. 23. – P. 184-197. – DOI: 10.1038/s41556-020-00619-0.

Maru Y., Kawata A., Taguchi A., Ishii Y., Baba S., Mori M., Nagamatsu T., Oda K., Kukimoto I., Osuga Y., et al. Establishment and molecular phenotyping of organoids from the squamocolumnar junction region of the uterine cervix // Cancers (Basel). – 2020. – V. 12. – P. 694. – DOI: 10.3390/cancers12030694.

Min J., Zhang C., Bliton R.J., Caldwell B., Caplan L., Presentation K.S., Park D.J., Kong S.H., Lee H.S., Washington M.K., et al. Dysplastic stem cell plasticity functions as a driving force for neoplastic transformation of precancerous gastric mucosa // Gastroenterology. – 2022. – V. 163. – P. 875-890. – DOI: 10.1053/j.gastro.2022.06.021.

Busslinger G.A., de Barbanson B., Oka R., Weusten B.L.A., de Maat M., van Hillegersberg R., Brosens L.A.A., van Boxtel R., van Oudenaarden A., Clevers H. Molecular characterization of Barrett's esophagus at single-cell resolution // Proc Natl Acad Sci USA. – 2021. – V. 118. – DOI: 10.1073/pnas.2113061118.

Nguyen L., Jager M., Lieshout R., de Ruiter P.E., Locati M.D., Besselink N., van der Roest B., Janssen R., Boymans S., de Jonge J., et al. Precancerous liver diseases do not cause increased mutagenesis in liver stem cells // Commun Biol. – 2021. – V. 4. – P. 1301. – DOI: 10.1038/s42003-021-02839-y.

Rosenbluth J.M., Schackmann R.C.J., Gray G.K., Selfors L.M., Li C.M., Boedicker M., Kuiken H.J., Richardson A., Brock J., Garber J., et al. Organoid cultures from normal and cancer-prone human breast tissues preserve complex epithelial lineages // Nat Commun. – 2020. – V. 11. – P. 1711. – DOI: 10.1038/s41467-020-15548-7.

B.C.H. Lee, P.S. Robinson, T.H.H. Coorens, H.H.N. Yan, S. Olafsson, H. Lee-Six, M.A. Sanders, H.C. Siu, J. Hewinson, S.S.K. Yue, et al. Mutational landscape of normal epithelial cells in Lynch syndrome patients. Nat. Commun., 13 (2022), p. 2710. 10.1038/s41467-022-29920-2

G. Vlachogiannis, S. Hedayat, A. Vatsiou, Y. Jamin, J. Fernández-Mateos, K. Khan, A. Lampis, K. Eason, I. Huntingford, R. Burke, et al. Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science, 359 (2018), pp. 920-926. 10.1126/science.aao2774

M. Crespo, E. Vilar, S.Y. Tsai, K. Chang, S. Amin, T. Srinivasan, T. Zhang, N.H. Pipalia, H.J. Chen, M. Witherspoon, et al. Colonic organoids derived from human induced pluripotent stem cells for modeling colorectal cancer and drug testing. Nat. Med., 23 (2017), pp. 878-884. 10.1038/nm.4355

N. Yucer, R. Ahdoot, M.J. Workman, A.H. Laperle, M.S. Recouvreux, K. Kurowski, D.J. Naboulsi, V. Liang, Y. Qu, J.T. Plummer, et al. Human iPSC-derived fallopian tube organoids with BRCA1 mutation recapitulate early-stage carcinogenesis. Cell Rep., 37 (2021), p. 110146. 10.1016/j.celrep.2021.110146

M. Breunig, J. Merkle, M. Wagner, M.K. Melzer, T.F.E. Barth, T. Engleitner, J. Krumm, S. Wiedenmann, C.M. Cohrs, L. Perkhofer, et al. Modeling plasticity and dysplasia of pancreatic ductal organoids derived from human pluripotent stem cells. Cell Stem Cell, 28 (2021), pp. 1105-1124. 10.1016/j.stem.2021.03.005

E. Driehuis, K. Kretzschmar, H. Clevers. Establishment of patient-derived cancer organoids for drug-screening applications. Nat. Protoc., 15 (2020), pp. 3380-3409. 10.1038/s41596-020-0379-4

M. Fujii, T. Sato. Somatic cell-derived organoids as prototypes of human epithelial tissues and diseases. Nat. Mater., 20 (2021), pp. 156-169. 10.1038/s41563-020-0754-0

P. Jung, T. Sato, A. Merlos-Suárez, F.M. Barriga, M. Iglesias, D. Rossell, H. Auer, M. Gallardo, M.A. Blasco, E. Sancho, et al. Isolation and in vitro expansion of human colonic stem cells. Nat. Med., 17 (2011), pp. 1225-1227. 10.1038/nm.2470

L. Broutier, A. Andersson-Rolf, C.J. Hindley, S.F. Boj, H. Clevers, B.K. Koo, M. Huch. Culture and establishment of self-renewing human and mouse adult liver and pancreas 3D organoids and their genetic manipulation. Nat. Protoc., 11 (2016), pp. 1724-1743. 10.1038/nprot.2016.097

J.F. Dekkers, E.J. van Vliet, N. Sachs, J.M. Rosenbluth, O. Kopper, H.G. Rebel, E.J. Wehrens, C. Piani, J.E. Visvader, C.S. Verissimo, et al. Long-term culture, genetic manipulation and xenotransplantation of human normal and breast cancer organoids. Nat. Protoc., 16 (2021), pp. 1936-1965. 10.1038/s41596-020-00474-1

M. Fujii, M. Matano, K. Toshimitsu, A. Takano, Y. Mikami, S. Nishikori, S. Sugimoto, T. Sato. Human intestinal organoids maintain self-renewal capacity and cellular diversity in niche-inspired culture condition. Cell Stem Cell, 23 (2018), pp. 787-793. 10.1016/j.stem.2018.11.016

H. Hu, H. Gehart, B. Artegiani, C. LÖpez-Iglesias, F. Dekkers, O. Basak, J. van Es, S.M. Chuva de Sousa Lopes, H. Begthel, J. Korving, et al. Long-term expansion of functional mouse and human hepatocytes as 3D organoids. Cell, 175 (2018), pp. 1591-1606. 10.1016/j.cell.2018.11.013

M. Jiang, H. Li, Y. Zhang, Y. Yang, R. Lu, K. Liu, S. Lin, X. Lan, H. Wang, H. Wu, et al. Transitional basal cells at the squamous-columnar junction generate Barrett's oesophagus. Nature, 550 (2017), pp. 529-533. 10.1038/nature24269

Transitional basal cells at the squamous-columnar junction generate Barrett's oesophagus. Nature, 550 (2017), pp. 529-533. 10.1038/nature24269

W.R. Karthaus, P.J. Iaquinta, J. Drost, A. Gracanin, R. van Boxtel, J. Wongvipat, C.M. Dowling, D. Gao, H. Begthel, N. Sachs, et al. Identification of multipotent luminal progenitor cells in human prostate organoid cultures. Cell, 159 (2014), pp. 163-175. 10.1016/j.cell.2014.08.017

F. Schutgens, M.B. Rookmaaker, T. Margaritis, A. Rios, C. Ammerlaan, J. Jansen, L. Gijzen, M. Vormann, A. Vonk, M. Viveen, et al. Tubuloids derived from human adult kidney and urine for personalized disease modeling. Nat. Biotechnol., 37 (2019), pp. 303-313. 10.1038/s41587-019-0048-8

M. Huch, H. Gehart, R. van Boxtel, K. Hamer, F. Blokzijl, M.M. Verstegen, E. Ellis, M. van Wenum, S.A. Fuchs, J. de Ligt, et al. Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell, 160 (2015), pp. 299-312. 10.1016/j.cell.2014.11.050

O.A. Timofeeva, N. Palechor-Ceron, G. Li, H. Yuan, E. Krawczyk, X. Zhong, G. Liu, G. Upadhyay, A. Dakic, S. Yu, et al. Conditionally reprogrammed normal and primary tumor prostate epithelial cells: a novel patient-derived cell model for studies of human prostate cancer. Oncotarget, 8 (2017), pp. 22741-22758. 10.18632/oncotarget.13937

X. Liu, E. Krawczyk, F.A. Suprynowicz, N. Palechor-Ceron, H. Yuan, A. Dakic, V. Simic, Y.L. Zheng, P. Sripadhan, C. Chen, et al. Conditional reprogramming and long-term expansion of normal and tumor cells from human biospecimens. Nat. Protoc., 12 (2017), pp. 439-451. 10.1038/nprot.2016.174

B.R.S. Correa, J. Hu, L.O.F. Penalva, R. Schlegel, D.L. Rimm, P.A.F. Galante, S. Agarwal. Patient-derived conditionally reprogrammed cells maintain intra-tumor genetic heterogeneity. Sci. Rep., 8 (2018), p. 4097. 10.1038/s41598-018-22427-1

C. Chen, S. Choudhury, D. Wangsa, C.J. Lescott, D.J. Wilkins, P. Sripadhan, X. Liu, D. Wangsa, T. Ried, C. Moskaluk, et al. A multiplex preclinical model for adenoid cystic carcinoma of the salivary gland identifies regorafenib as a potential therapeutic drug. Sci. Rep., 7 (2017), p. 11410. 10.1038/s41598-017-11764-2

S. Raghavan, P.S. Winter, A.W. Navia, H.L. Williams, A. DenAdel, K.E. Lowder, J. GalvezReyes, R.L. Kalekar, N. Mulugeta, K.S. Kapner, et al. Microenvironment drives cell state, plasticity, and drug response in pancreatic cancer. Cell, 184 (2021), pp. 6119-6137. 10.1016/j.cell.2021.11.017

K. Miyabayashi, L.A. Baker, A. Deschênes, B. Traub, G. Caligiuri, D. Plenker, B. Alagesan, P. Belleau, S. Li, J. Kendall, et al. Intraductal transplantation models of human pancreatic ductal adenocarcinoma reveal progressive transition of molecular subtypes. Cancer Discov., 10 (2020), pp. 1566-1589. 10.1158/2159-8290.CD-20-0133

C. Cortina, G. Turon, D. Stork, X. Hernando-Momblona, M. Sevillano, M. Aguilera, S. Tosi, A. Merlos-Suárez, C. Stephan-Otto Attolini, E. Sancho, et al. A genome editing approach to study cancer stem cells in human tumors. EMBO Mol. Med., 9 (2017), pp. 869-879. 10.15252/emmm.201707550

de Sousa, F. Melo, A.V. Kurtova, J.M. Harnoss, N. Kljavin, J.D. Hoeck, J. Hung, J.E. Anderson, E.E. Storm, Z. Modrusan, et al. A distinct role for Lgr5(+) stem cells in primary and metastatic colon cancer. Nature, 543 (2017), pp. 676-680. 10.1038/nature21713

M. Shimokawa, Y. Ohta, S. Nishikori, M. Matano, A. Takano, M. Fujii, S. Date, S. Sugimoto, T. Kanai, T. Sato. Visualization and targeting of LGR5(+) human colon cancer stem cells. Nature, 545 (2017), pp. 187-192. 10.1038/nature22081

A. Fumagalli, K.C. Oost, L. Kester, J. Morgner, L. Bornes, L. Bruens, L. Spaargaren, M. Azkanaz, T. Schelfhorst, E. Beerling, et al. Plasticity of Lgr5-negative cancer cells drives metastasis in colorectal cancer. Cell Stem Cell, 26 (2020), pp. 569-578. 10.1016/j.stem.2020.02.008

Y. Ohta, M. Fujii, S. Takahashi, A. Takano, K. Nanki, M. Matano, H. Hanyu, M. Saito, M. Shimokawa, S. Nishikori, et al. Cell-matrix interface regulates dormancy in human colon cancer stem cells. Nature, 608 (2022), pp. 784-794. 10.1038/s41586-022-05043-y

A. Alvarez-Varela, L. Novellasdemunt, F.M. Barriga, X. Hernando-Momblona, A. CanellasSocias, S. Cano-Crespo, M. Sevillano, C. Cortina, D. Stork, C. Morral, et al. Mex3a marks drug-tolerant persister colorectal cancer cells that mediate relapse after chemotherapy. Nat Cancer, 3 (2022), pp. 10521070. 10.1038/s43018-022-00402-0

A. Cañellas-Socias, C. Cortina, X. Hernando-Momblona, S. Palomo-Ponce, E.J. Mulholland, G. Turon, L. Mateo, S. Conti, O. Roman, M. Sevillano, et al. Metastatic recurrence in colorectal cancer arises from residual EMP1(+) cells. Nature, 611 (2022), pp. 603-613. 10.1038/s41586-022-05402-9

K. Nanki, M. Fujii, M. Shimokawa, M. Matano, S. Nishikori, S. Date, A. Takano, K. Toshimitsu, Y. Ohta, S. Takahashi, et al. Somatic inflammatory gene mutations in human ulcerative colitis epithelium. Nature, 577 (2020), pp. 254-259. 10.1038/s41586-019-1844-5

N. Kakiuchi, K. Yoshida, M. Uchino, T. Kihara, K. Akaki, Y. Inoue, K. Kawada, S. Nagayama, A. Yokoyama, S. Yamamoto, et al. Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis. Nature, 577 (2020), pp. 260-265. 10.1038/s41586-019-1856-1

S. Olafsson, R.E. McIntyre, T. Coorens, T. Butler, H. Jung, P.S. Robinson, H. Lee-Six, M.A. Sanders, K. Arestang, C. Dawson, et al. Somatic evolution in non-neoplastic IBD-affected colon. Cell, 182 (2020), pp. 672–684.e11. 10.1016/j.cell.2020.06.036

J. Drost, R. van Boxtel, F. Blokzijl, T. Mizutani, N. Sasaki, V. Sasselli, J. de Ligt, S. Behjati, J.E. Grolleman, T. van Wezel, et al. Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer. Science, 358 (2017), pp. 234-238. 10.1126/science.aao3130

H. Fang, H.H.N. Yan, R.A. Bilardi, C. Flensburg, H. Yang, J.A. Barbour, H.C. Siu, M. Turski, E. Chew, Z. Xu, et al. Ganciclovir-induced mutations are present in a diverse spectrum of post-transplant malignancies. Genome Med., 14 (2022), p. 124. 10.1186/s13073-022-01131-w

C. Pleguezuelos-Manzano, J. Puschhof, A. Rosendahl Huber, A. van Hoeck, H.M. Wood, J. Nomburg, C. Gurjao, F. Manders, G. Dalmasso, P.B. Stege, et al. Mutational signature in colorectal cancer caused by genotoxic pks(+) E. coli. Nature, 580 (2020), pp. 269-273. 10.1038/s41586-020-2080-8

K.W. McCracken, E.M. Catá, C.M. Crawford, K.L. Sinagoga, M. Schumacher, B.E. Rockich, Y.H. Tsai, C.N. Mayhew, J.R. Spence, Y. Zavros, et al. Modelling human development and disease in pluripotent stem-cell-derived gastric organoids. Nature, 516 (2014), pp. 400-404. 10.1038/nature13863

100

E. De Crignis, T. Hossain, S. Romal, F. Carofiglio, P. Moulos, M.M. Khalid, S. Rao, A. Bazrafshan, M.M. Verstegen, F. Pourfarzad, et al. Application of human liver organoids as a patientderived primary model for HBV infection and related hepatocellular carcinoma. eLife, 10 (2021), 10.7554/eLife.60747. 10.7554/eLife.60747

101

Y.Z. Nie, Y.W. Zheng, K. Miyakawa, S. Murata, R.R. Zhang, K. Sekine, Y. Ueno, T. Takebe, T. Wakita, A. Ryo, et al. Recapitulation of hepatitis B virus-host interactions in liver organoids from human induced pluripotent stem cells. EBiomedicine, 35 (2018), pp. 114-123. 10.1016/j.ebiom.2018.08.014

102

A.A. Duarte, E. Gogola, N. Sachs, M. Barazas, S. Annunziato, J.R. de Ruiter, A. Velds, S. Blatter, J.M. Houthuijzen, M. van de Ven, et al. BRCA-deficient mouse mammary tumor organoids to study cancer-drug resistance. Nat Methods, 15 (2018), pp. 134-140. 10.1038/nmeth.4535

103

D.V.F. Tauriello, S. Palomo-Ponce, D. Stork, A. Berenguer-Llergo, J. Badia-Ramentol, M. Iglesias, M. Sevillano, S. Ibiza, A. Cañellas, X. Hernando-Momblona, et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature, 554 (2018), pp. 538-543. 10.1038/nature25492

104

D.J. Flanagan, N. Pentinmikko, K. Luopajärvi, N.J. Willis, K. Gilroy, A.P. Raven, L. McGarry, J.I. Englund, A.T. Webb, S. Scharaw, et al. NOTUM from Apc-mutant cells biases clonal competition to initiate cancer. Nature, 594 (2021), pp. 430-435. 10.1038/s41586-021-03525-z

105

S.M. van Neerven, N.E. de Groot, L.E. Nijman, B.P. Scicluna, M.S. van Driel, M.C. Lecca, D.O. Warmerdam, V. Kakkar, L.F. Moreno, F.A. Vieira Braga, et al. Apc-mutant cells act as supercompetitors in intestinal tumour initiation. Nature, 594 (2021), pp. 436-441. 10.1038/s41586-02103558-4

106

K.P. O'Rourke, E. Loizou, G. Livshits, E.M. Schatoff, T. Baslan, E. Manchado, J. Simon, P.B. Romesser, B. Leach, T. Han, et al. Transplantation of engineered organoids enables rapid generation of metastatic mouse models of colorectal cancer. Nat. Biotechnol., 35 (2017), pp. 577-582. 10.1038/nbt.3837

107

J. Roper, T. Tammela, N.M. Cetinbas, A. Akkad, A. Roghanian, S. Rickelt, M. Almeqdadi, K. Wu, M.A. Oberli, F.J. Sánchez-Rivera, et al. In vivo genome editing and organoid transplantation models of colorectal cancer and metastasis. Nat. Biotechnol., 35 (2017), pp. 569-576. 10.1038/nbt.3836

108

S. Zhang, S. Iyer, H. Ran, I. Dolgalev, S. Gu, W. Wei, C.J.R. Foster, C.A. Loomis, N. Olvera, F. Dao, et al. Genetically defined, syngeneic organoid platform for developing combination therapies for ovarian cancer. Cancer Discov., 11 (2021), pp. 362-383. 10.1158/2159-8290.CD-20-0455

109

S. Naranjo, C.M. Cabana, L.M. LaFave, R. Romero, S.L. Shanahan, A. Bhutkar, P.M.K. Westcott, J.M. Schenkel, A. Ghosh, L.Z. Liao, et al. Modeling diverse genetic subtypes of lung adenocarcinoma with a next-generation alveolar type 2 organoid platform. Genes Dev., 36 (2022), pp. 936949. 10.1101/gad.349659.122

110

Drost, R.H. van Jaarsveld, B. Ponsioen, C. Zimberlin, R. van Boxtel, A. Buijs, N. Sachs, R.M. Overmeer, G.J. Offerhaus, H. Begthel, et al. Sequential cancer mutations in cultured human intestinal stem cells. Nature, 521 (2015), pp. 43-47. 10.1038/nature14415

111

M. Matano, S. Date, M. Shimokawa, A. Takano, M. Fujii, Y. Ohta, T. Watanabe, T. Kanai, T. Sato. Modeling colorectal cancer using CRISPR-Cas9-mediated engineering of human intestinal organoids. Nat. Med., 21 (2015), pp. 256-262. 10.1038/nm.3802

112

A. Fumagalli, J. Drost, S.J. Suijkerbuijk, R. van Boxtel, J. de Ligt, G.J. Offerhaus, H. Begthel, E. Beerling, E.H. Tan, O.J. Sansom, et al. Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids. Proc. Natl. Acad. Sci. USA, 114 (2017), pp. E2357-E2364. 10.1073/pnas.1701219114

113

Arianna Fumagalli, Jarno Drost, Saskia J. E. Suijkerbuijk, Ruben van Boxtel, Joep de Ligt, G. Johan Offerhaus, Harry Begthel, Evelyne Beerling, Ee Hong Tan, Owen J. Sansom, Edwin Cuppen Hans Clevers h.clevers@hubrecht.eu, and Jacco van Rheenen Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids. https://orcid.org/0000-0002-0400-9542

114

A.F.M. Dost, A.L. Moye, M. Vedaie, L.M. Tran, E. Fung, D. Heinze, C. Villacorta-Martin, J. Huang, R. Hekman, J.H. Kwan, et al. Organoids model transcriptional hallmarks of oncogenic KRAS activation in lung epithelial progenitor cells. Cell Stem Cell, 27 (2020), pp. 663-678. 10.1016/j.stem.2020.07.022

115

J.F. Dekkers, J.R. Whittle, F. Vaillant, H.R. Chen, C. Dawson, K. Liu, M.H. Geurts, M.J. Herold, H. Clevers, G.J. Lindeman, et al. Modeling breast cancer using CRISPR-Cas9-mediated engineering of human breast organoids. J. Natl. Cancer Inst., 112 (2020), pp. 540-544. 10.1093/jnci/djz196

116

J. Ogawa, G.M. Pao, M.N. Shokhirev, I.M. Verma. Glioblastoma model using human cerebral organoids. Cell Rep., 23 (2018), pp. 1220-1229. 10.1016/j.celrep.2018.03.105

117

S. Bian, M. Repic, Z. Guo, A. Kavirayani, T. Burkard, J.A. Bagley, C. Krauditsch, J.A. Knoblich. Genetically engineered cerebral organoids model brain tumor formation. Nat. Methods, 15 (2018), pp. 631-639. 10.1038/s41592-018-0070-7

118

B. Artegiani, L. van Voorthuijsen, R.G.H. Lindeboom, D. Seinstra, I. Heo, P. Tapia, C. LópezIglesias, D. Postrach, T. Dayton, R. Oka, et al. Probing the tumor suppressor function of BAP1 in CRISPRengineered human liver organoids. Cell Stem Cell, 24 (2019), pp. 927-943. 10.1016/j.stem.2019.04.017

119

K. Kawasaki, M. Fujii, S. Sugimoto, K. Ishikawa, M. Matano, Y. Ohta, K. Toshimitsu, S. Takahashi, N. Hosoe, S. Sekine, et al. Chromosome engineering of human colon-derived organoids to develop a model of traditional serrated adenoma. Gastroenterology, 158 (2020), pp. 638-651. 10.1053/j.gastro.2019.10.009

120

Y.H. Lo, K.S. Kolahi, Y. Du, C.Y. Chang, A. Krokhotin, A. Nair, W.D. Sobba, K. Karlsson, S.J. Jones, T.A. Longacre, et al. A CRISPR/Cas9-engineered ARID1A-deficient human gastric cancer organoid model reveals essential and nonessential modes of oncogenic transformation. Cancer Discov., 11 (2021), pp. 1562-1581. 10.1158/2159-8290.CD-20-1109

121

Z. Wu, J. Zhou, X. Zhang, Z. Zhang, Y. Xie, J.B. Liu, Z.V. Ho, A. Panda, X. Qiu, P. Cejas, et al. Reprogramming of the esophageal squamous carcinoma epigenome by SOX2 promotes ADAR1 dependence. Nat. Genet., 53 (2021), pp. 881-894. 10.1038/s41588-021-00859-2

122

H. Liu, Y. Zhang, Y.Y. Zhang, Y.P. Li, Z.Q. Hua, C.J. Zhang, K.C. Wu, F. Yu, Y. Zhang, J. Su, et al. Human embryonic stem cell-derived organoid retinoblastoma reveals a cancerous origin. Proc. Natl. Acad. Sci. USA., 117 (2020), pp. 33628-33638. 10.1073/pnas.2011780117

123

E. Fessler, J. Drost, S.R. van Hooff, J.F. Linnekamp, X. Wang, M. Jansen, F. De Sousa E Melo, P.R. Prasetyanti, J.E. IJspeert, M. Franitza, et al. TGFβ signaling directs serrated adenomas to the mesenchymal colorectal cancer subtype. EMBO Mol. Med., 8 (2016), pp. 745-760. 10.15252/emmm.201606184

124

B.E. Michels, M.H. Mosa, B.I. Streibl, T. Zhan, C. Menche, K. Abou-El-Ardat, T. Darvishi, E. Członka, S. Wagner, J. Winter, et al. Pooled in vitro and in vivo CRISPR-Cas9 screening identifies tumor suppressors in human colon organoids. Cell Stem Cell, 26 (2020), pp. 782–792.e7. 10.1016/j.stem.2020.04.003

125

T. Ringel, N. Frey, F. Ringnalda, S. Janjuha, S. Cherkaoui, S. Butz, S. Srivatsa, M. Pirkl, G. Russo, L. Villiger, et al. Genome-scale CRISPR screening in human intestinal organoids identifies drivers.

126

K. Murakami, Y. Terakado, K. Saito, Y. Jomen, H. Takeda, M. Oshima, N. Barker. A genome-scale CRISPR screen reveals factors regulating Wnt-dependent renewal of mouse gastric epithelial cells. Proc. Natl. Acad. Sci. USA, 118 (2021), 10.1073/pnas.2016806118

127

H.A. McCauley, J.M. Wells. Pluripotent stem cell-derived organoids: using principles of developmental biology to grow human tissues in a dish. Development, 144 (2017), pp. 958-962. 10.1242/dev.140731

128

J.R. Spence, C.N. Mayhew, S.A. Rankin, M.F. Kuhar, J.E. Vallance, K. Tolle, E.E. Hoskins, V.V. Kalinichenko, S.I. Wells, A.M. Zorn, et al. Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature, 470 (2011), pp. 105-109. 10.1038/nature09691

129

Y. Shi, H. Inoue, J.C. Wu, S. Yamanaka. Induced pluripotent stem cell technology: a decade of progress. Nat. Rev. Drug Discov., 16 (2017), pp. 115-130. 10.1038/nrd.2016.245

130

R.C. Smith, V. Tabar. Constructing and deconstructing cancers using human pluripotent stem cells and organoids. Cell Stem Cell, 24 (2019), pp. 2-24. 10.1016/j.stem.2018.11.012

131

M.A. Lancaster, M. Renner, C.A. Martin, D. Wenzel, L.S. Bicknell, M.E. Hurles, T. Homfray, J.M. Penninger, A.P. Jackson, J.A. Knoblich. Cerebral organoids model human brain development and microcephaly. Nature, 501 (2013), pp. 373-379. 10.1038/nature12517

132

Y.W. Chen, S.X. Huang, A.L.R.T. de Carvalho, S.H. Ho, M.N. Islam, S. Volpi, L.D. Notarangelo, M. Ciancanelli, J.L. Casanova, J. Bhattacharya, et al. A three-dimensional model of human lung development and disease from pluripotent stem cells. Nat. Cell Biol., 19 (2017), pp. 542-549. 10.1038/ncb3510

133

M. Hohwieler, A. Illing, P.C. Hermann, T. Mayer, M. Stockmann, L. Perkhofer, T. Eiseler, J.S. Antony, M. Müller, S. Renz, et al. Human pluripotent stem cell-derived acinar/ductal organoids generate human pancreas upon orthotopic transplantation and allow disease modelling. Gut, 66 (2017), pp. 473486. 10.1136/gutjnl-2016-312423

134

S.L. Trisno, K.E.D. Philo, K.W. McCracken, E.M. Catá, S. Ruiz-Torres, S.A. Rankin, L. Han, T. Nasr, P. Chaturvedi, M.E. Rothenberg, et al. Esophageal organoids from human pluripotent stem cells delineate Sox2 functions during esophageal specification. Cell Stem Cell, 23 (2018), pp. 501–515.e7. 10.1016/j.stem.2018.08.008

135

J.H. Low, P. Li, E.G.Y. Chew, B. Zhou, K. Suzuki, T. Zhang, M.M. Lian, M. Liu, E. Aizawa, C. Rodriguez Esteban, et al. Generation of human PSC-derived kidney organoids with patterned nephron segments and a de novo vascular network. Cell Stem Cell, 25 (2019), pp. 373–387.e9. 10.1016/j.stem.2019.06.009

136

S.J. Mun, J.S. Ryu, M.O. Lee, Y.S. Son, S.J. Oh, H.S. Cho, M.Y. Son, D.S. Kim, S.J. Kim, H.J. Yoo, et al. Generation of expandable human pluripotent stem cell-derived hepatocyte-like liver organoids. J. Hepatol., 71 (2019), pp. 970-985. 10.1016/j.jhep.2019.06.030

137

M. Zhang, J.J. Vandana, L. Lacko, S. Chen. Modeling cancer progression using human pluripotent stem cell-derived cells and organoids. Stem Cell Res., 49 (2020), p. 102063. 10.1016/j.scr.2020.102063

138

M.P. Chao, A.J. Gentles, S. Chatterjee, F. Lan, A. Reinisch, M.R. Corces, S. Xavy, J. Shen, D. Haag, S. Chanda, et al. Human AML-iPSCs reacquire leukemic properties after differentiation and model clonal variation of disease. Cell Stem Cell, 20 (2017), pp. 329–344.e7. 10.1016/j.stem.2016.11.018

139

K. Kumano, S. Arai, M. Hosoi, K. Taoka, N. Takayama, M. Otsu, G. Nagae, K. Ueda, K. Nakazaki, Y. Kamikubo, et al. Generation of induced pluripotent stem cells from primary chronic myelogenous leukemia patient samples. Blood, 119 (2012), pp. 6234-6242. 10.1182/blood-2011-07-367441

140

K. Hu, J. Yu, K. Suknuntha, S. Tian, K. Montgomery, K.D. Choi, R. Stewart, J.A. Thomson, I.I. Slukvin. Efficient generation of transgene-free induced pluripotent stem cells from normal and neoplastic bone marrow and cord blood mononuclear cells. Blood, 117 (2011), pp. e109-e119. 10.1182/blood2010-07-298331

141

S. Gandre-Babbe, P. Paluru, C. Aribeana, S.T. Chou, S. Bresolin, L. Lu, S.K. Sullivan, S.K. Tasian, J. Weng, H. Favre, et al. Patient-derived induced pluripotent stem cells recapitulate hematopoietic abnormalities of juvenile myelomonocytic leukemia. Blood, 121 (2013), pp. 4925-4929. 10.1182/blood2013-01-478412

142

A. Linkous, D. Balamatsias, M. Snuderl, L. Edwards, K. Miyaguchi, T. Milner, B. Reich, L. Cohen-Gould, A. Storaska, Y. Nakayama, et al. Modeling patient-derived glioblastoma with cerebral organoids. Cell Rep., 26 (2019), pp. 3203–3211.e5. 10.1016/j.celrep.2019.02.063

143

M.S. Choe, J.S. Kim, H.C. Yeo, C.M. Bae, H.J. Han, K. Baek, W. Chang, K.S. Lim, S.P. Yun, I.S. Shin, et al. A simple metastatic brain cancer model using human embryonic stem cell-derived cerebral organoids. FASEB J., 34 (2020), pp. 16464-16475. 10.1096/fj.202000372R

144

J. Barretina, G. Caponigro, N. Stransky, K. Venkatesan, A.A. Margolin, S. Kim, C.J. Wilson, J. Lehár, G.V. Kryukov, D. Sonkin, et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature, 483 (2012), pp. 603-607. 10.1038/nature11003

145

M.J. Garnett, E.J. Edelman, S.J. Heidorn, C.D. Greenman, A. Dastur, K.W. Lau, P. Greninger, I.R. Thompson, X. Luo, J. Soares, et al. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature, 483 (2012), pp. 570-575. 10.1038/nature11005

146

L. Li, H. Knutsdottir, K. Hui, M.J. Weiss, J. He, B. Philosophe, A.M. Cameron, C.L. Wolfgang, T.M. Pawlik, G. Ghiaur, et al. Human primary liver cancer organoids reveal intratumor and interpatient drug response heterogeneity. JCI Insight, 4 (2019), 10.1172/jci.insight.121490

147

C.J. de Witte, J. Espejo Valle-Inclan, N. Hami, K. Lõhmussaar, O. Kopper, C.P.H. Vreuls, G.N. Jonges, P. van Diest, L. Nguyen, H. Clevers, et al. Patient-derived ovarian cancer organoids mimic clinical response and exhibit heterogeneous inter- and intrapatient drug responses. Cell Rep., 31 (2020), p. 107762. 10.1016/j.celrep.2020.107762

148

S. Karkampouna, F. La Manna, A. Benjak, M. Kiener, M. De Menna, E. Zoni, J. Grosjean, I. Klima, A. Garofoli, M. Bolis, et al. Patient-derived xenografts and organoids model therapy response in prostate cancer. Nat. Commun., 12 (2021), p. 1117. 10.1038/s41467-021-21300-6

149

J. Betge, N. Rindtorff, J. Sauer, B. Rauscher, C. Dingert, H. Gaitantzi, F. Herweck, K. SrourMhanna, T. Miersch, E. Valentini, et al. The drug-induced phenotypic landscape of colorectal cancer organoids. Nat. Commun., 13 (2022), p. 3135. 10.1038/s41467-022-30722-9

150

K. Toshimitsu, A. Takano, M. Fujii, K. Togasaki, M. Matano, S. Takahashi, T. Kanai, T. Sato. Organoid screening reveals epigenetic vulnerabilities in human colorectal cancer. Nat. Chem. Biol., 18 (2022), pp. 605-614. 10.1038/s41589-022-00984-x

151

S.N. Ooft, F. Weeber, K.K. Dijkstra, C.M. McLean, S. Kaing, E. van Werkhoven, L. Schipper, L. Hoes, D.J. Vis, J. van de Haar, et al. Patient-derived organoids can predict response to chemotherapy in metastatic colorectal cancer patients. Sci. Transl. Med., 11 (2019), 10.1126/scitranslmed.aay2574

152

C. Calandrini, S.R. van Hooff, I. Paassen, D. Ayyildiz, S. Derakhshan, M.E.M. Dolman, K.P.S. Langenberg, M. van de Ven, C. de Heus, N. Liv, et al. Organoid-based drug screening reveals Neddylation as therapeutic target for malignant rhabdoid tumors. Cell Rep., 36 (2021), p. 109568. 10.1016/j.celrep.2021.109568

153

P. Tan, M. Wang, A. Zhong, Y. Wang, J. Du, J. Wang, L. Qi, Z. Bi, P. Zhang, T. Lin, et al. SRT1720 inhibits the growth of bladder cancer in organoids and murine models through the SIRT1-HIF axis. Oncogene, 40 (2021), pp. 6081-6092. 10.1038/s41388-021-01999-9

154

T. Seidlitz, Y.T. Chen, H. Uhlemann, S. Schölch, S. Kochall, S.R. Merker, A. Klimova, A. Hennig, C. Schweitzer, K. Pape, et al. Mouse models of human gastric cancer subtypes with stomachspecific CreERT2-mediated pathway alterations. Gastroenterology, 157 (2019), pp. 1599–1614.e2. 10.1053/j.gastro.2019.09.026

155

H. Zhang, A. Schaefer, Y. Wang, R.G. Hodge, D.R. Blake, J.N. Diehl, A.G. Papageorge, M.D. Stachler, J. Liao, J. Zhou, et al. Gain-of-function RHOA mutations promote focal adhesion kinase activation and dependency in diffuse gastric cancer. Cancer Discov., 10 (2020), pp. 288-305. 10.1158/21598290.CD-19-0811

156

S. Sugimoto, Y. Ohta, M. Fujii, M. Matano, M. Shimokawa, K. Nanki, S. Date, S. Nishikori, Y. Nakazato, T. Nakamura, et al. Reconstruction of the human colon epithelium in vivo. Cell Stem Cell, 22 (2018), pp. 171–176.e5. 10.1016/j.stem.2017.11.012

157

K. Karlsson, M. Przybilla, H. Xu, E. Kotler, K. Karagyozova, A. Sockell, K. Liu, A. Mah, Y.H. Lo, B. Lu, et al. Experimental evolution in TP53 deficient human gastric organoids recapitulates tumorigenesis. Preprint at bioRxiv (2022), 10.1101/2022.04.09.487529

158

R. Coppo, J. Kondo, K. Iida, M. Okada, K. Onuma, Y. Tanaka, M. Kamada, M. Ohue, K. Kawada, K. Obama, et al. Distinct but interchangeable subpopulations of colorectal cancer cells with different growth fates and drug sensitivity. iScience, 26 (2023), p. 105962. 10.1016/j.isci.2023.105962

159

K.K. Dijkstra, C.M. Cattaneo, F. Weeber, M. Chalabi, J. van de Haar, L.F. Fanchi, M. Slagter, D.L. van der Velden, S. Kaing, S. Kelderman, et al. Generation of tumor-reactive T cells by co-culture of peripheral blood lymphocytes and tumor organoids. Cell, 174 (2018), pp. 1586–1598.e12. 10.1016/j.cell.2018.07.009

160

B. Palikuqi, D.T. Nguyen, G. Li, R. Schreiner, A.F. Pellegata, Y. Liu, D. Redmond, F. Geng, Y. Lin, J.M. Gómez-Salinero, et al. Adaptable haemodynamic endothelial cells for organogenesis and tumorigenesis. Nature, 585 (2020), pp. 426-432. 10.1038/s41586-020-2712-z

161

J.T. Neal, X. Li, J. Zhu, V. Giangarra, C.L. Grzeskowiak, J. Ju, I.H. Liu, S.H. Chiou, A.A. Salahudeen, A.R. Smith, et al. Organoid modeling of the tumor immune microenvironment. Cell, 175 (2018), pp. 1972–1988.e16. 10.1016/j.cell.2018.11.021

162

S. Ding, C. Hsu, Z. Wang, N.R. Natesh, R. Millen, M. Negrete, N. Giroux, G.O. Rivera, A. Dohlman, S. Bose, et al. Patient-derived micro-organospheres enable clinical precision oncology. Cell Stem Cell, 29 (2022), pp. 905–917.e6. 10.1016/j.stem.2022.04.006

163

N.S. Münch, H.Y. Fang, J. Ingermann, H.C. Maurer, A. Anand, V. Kellner, V. Sahm, M. Wiethaler, T. Baumeister, F. Wein, et al. High-fat diet accelerates carcinogenesis in a mouse model of Barrett's esophagus via interleukin 8 and alterations to the gut microbiome. Gastroenterology, 157 (2019), pp. 492-506.e2. 10.1053/j.gastro.2019.04.013

164

S. Price, S. Bhosle, E. Gonçalves, X. Li, D.P. McClurg, S. Barthorpe, A. Beck, C. Hall, H. Lightfoot, L. Farrow, et al. A suspension technique for efficient large-scale cancer organoid culturing and perturbation screens. Sci. Rep., 12 (2022), p. 5571. 10.1038/s41598-022-09508-y

165

N. Gjorevski, N. Sachs, A. Manfrin, S. Giger, M.E. Bragina, P. Ordóñez-Morán, H. Clevers, M.P. Lutolf. Designer matrices for intestinal stem cell and organoid culture. Nature, 539 (2016), pp. 560564. 10.1038/nature20168

The authors declare that there are no conflicts of interest present.