{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T11:29:18Z","timestamp":1788348558684,"version":"build-2803163510"},"reference-count":57,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T00:00:00Z","timestamp":1757030400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Yonsei University College of Medicine","award":["6-2019-0139"],"award-info":[{"award-number":["6-2019-0139"]}]},{"name":"Yonsei University College of Medicine","award":["2018R1C1B6002732"],"award-info":[{"award-number":["2018R1C1B6002732"]}]},{"name":"Yonsei University College of Medicine","award":["RS-2025-00514263"],"award-info":[{"award-number":["RS-2025-00514263"]}]},{"name":"Yonsei University College of Medicine","award":["RS-2025-00514287"],"award-info":[{"award-number":["RS-2025-00514287"]}]},{"name":"Yonsei University College of Medicine","award":["RS-2023-00261343"],"award-info":[{"award-number":["RS-2023-00261343"]}]},{"name":"National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT","award":["6-2019-0139"],"award-info":[{"award-number":["6-2019-0139"]}]},{"name":"National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT","award":["2018R1C1B6002732"],"award-info":[{"award-number":["2018R1C1B6002732"]}]},{"name":"National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT","award":["RS-2025-00514263"],"award-info":[{"award-number":["RS-2025-00514263"]}]},{"name":"National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT","award":["RS-2025-00514287"],"award-info":[{"award-number":["RS-2025-00514287"]}]},{"name":"National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT","award":["RS-2023-00261343"],"award-info":[{"award-number":["RS-2023-00261343"]}]},{"name":"National Research Foundation of Korea (NRF)","award":["6-2019-0139"],"award-info":[{"award-number":["6-2019-0139"]}]},{"name":"National Research Foundation of Korea (NRF)","award":["2018R1C1B6002732"],"award-info":[{"award-number":["2018R1C1B6002732"]}]},{"name":"National Research Foundation of Korea (NRF)","award":["RS-2025-00514263"],"award-info":[{"award-number":["RS-2025-00514263"]}]},{"name":"National Research Foundation of Korea (NRF)","award":["RS-2025-00514287"],"award-info":[{"award-number":["RS-2025-00514287"]}]},{"name":"National Research Foundation of Korea (NRF)","award":["RS-2023-00261343"],"award-info":[{"award-number":["RS-2023-00261343"]}]},{"name":"Gene Editing\u2013Control\u2013Restoration Based Research Program","award":["6-2019-0139"],"award-info":[{"award-number":["6-2019-0139"]}]},{"name":"Gene Editing\u2013Control\u2013Restoration Based Research Program","award":["2018R1C1B6002732"],"award-info":[{"award-number":["2018R1C1B6002732"]}]},{"name":"Gene Editing\u2013Control\u2013Restoration Based Research Program","award":["RS-2025-00514263"],"award-info":[{"award-number":["RS-2025-00514263"]}]},{"name":"Gene Editing\u2013Control\u2013Restoration Based Research Program","award":["RS-2025-00514287"],"award-info":[{"award-number":["RS-2025-00514287"]}]},{"name":"Gene Editing\u2013Control\u2013Restoration Based Research Program","award":["RS-2023-00261343"],"award-info":[{"award-number":["RS-2023-00261343"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>MYCN amplification without concurrent RB1 mutations characterizes a rare yet highly aggressive subtype of retinoblastoma; however, its precise developmental origins and therapeutic vulnerabilities remain incompletely understood. Here, we modeled this subtype by lentiviral-mediated MYCN overexpression in human pluripotent stem cell-derived retinal organoids, revealing a discrete developmental window (days 70\u2013120) during which retinal progenitors showed heightened susceptibility to transformation. Tumors arising in this period exhibited robust proliferation, expressed SOX2, and lacked CRX, consistent with origin from primitive retinal progenitors. MYCN-overexpressing organoids generated stable cell lines that reproducibly gave rise to MYCN-driven tumors when xenografted into immunodeficient mice. Transcriptomic profiling demonstrated that MYCN-overexpressing organoids closely recapitulated molecular features of patient-derived MYCN-amplified retinoblastomas, particularly through activation of MYC\/E2F and mTORC1 signaling pathways. Pharmacological screening further identified distinct therapeutic vulnerabilities, demonstrating distinct subtype-specific sensitivity of MYCN-driven cells to transcriptional inhibitors (THZ1, Flavopiridol) and the cell-cycle inhibitor Volasertib, indicative of a unique oncogene-addicted state compared to RB1-deficient retinoblastoma cells. Collectively, our study elucidates the developmental and molecular mechanisms underpinning MYCN-driven retinoblastoma, establishes a robust and clinically relevant human retinal organoid platform, and highlights targeted transcriptional inhibition as a promising therapeutic approach for this aggressive pediatric cancer subtype.<\/jats:p>","DOI":"10.3390\/ijms26178675","type":"journal-article","created":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T14:53:01Z","timestamp":1757083981000},"page":"8675","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Human Retinal Organoid Modeling Defines Developmental Window and Therapeutic Vulnerabilities in MYCN-Amplified Retinoblastoma"],"prefix":"10.3390","volume":"26","author":[{"given":"Jinkyu","family":"Park","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Severance Eye Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7900-4159","authenticated-orcid":false,"given":"Gang","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Severance Eye Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiyun","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Biomedical Systems Informatics, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Jeong","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Severance Eye Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"},{"name":"Brain Korea 21 Project for Medical Science, Yonsei University, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6036-3397","authenticated-orcid":false,"given":"Minseok","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min Seok","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Severance Eye Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"},{"name":"Brain Korea 21 Project for Medical Science, Yonsei University, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeong Ah","family":"Lim","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Severance Eye Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"},{"name":"Brain Korea 21 Project for Medical Science, Yonsei University, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3142-6169","authenticated-orcid":false,"given":"Sanguk","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Severance Eye Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher Seungkyu","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Severance Eye Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1873-6959","authenticated-orcid":false,"given":"Min","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Institute of Vision Research, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5356-0827","authenticated-orcid":false,"given":"Sangwoo","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biomedical Systems Informatics, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0543-7132","authenticated-orcid":false,"given":"Junwon","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Institute of Vision Research, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suk Ho","family":"Byeon","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Severance Eye Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"},{"name":"Brain Korea 21 Project for Medical Science, Yonsei University, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/S1470-2045(13)70045-7","article-title":"Characterisation of retinoblastomas without rb1 mutations: Genomic, gene expression, and clinical studies","volume":"14","author":"Rushlow","year":"2013","journal-title":"Lancet Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Ruiz-Perez, M.V., Henley, A.B., and Arsenian-Henriksson, M. (2017). The mycn protein in health and disease. Genes, 8.","DOI":"10.3390\/genes8040113"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1101\/gad.1608008","article-title":"N-myc coordinates retinal growth with eye size during mouse development","volume":"22","author":"Martins","year":"2008","journal-title":"Genes Dev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"100188","DOI":"10.1016\/j.xops.2022.100188","article-title":"High-level mycn-amplified rb1-proficient retinoblastoma tumors retain distinct molecular signatures","volume":"2","author":"Roohollahi","year":"2022","journal-title":"Ophthalmol. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3868","DOI":"10.1167\/iovs.10-6501","article-title":"Sonoporation enhances chemotherapeutic efficacy in retinoblastoma cells in vitro","volume":"52","author":"Lee","year":"2011","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"109447","DOI":"10.1016\/j.exer.2023.109447","article-title":"The predictive capacity of in vitro preclinical models to evaluate drugs for the treatment of retinoblastoma","volume":"230","author":"Sinenko","year":"2023","journal-title":"Exp. Eye Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1159\/000370156","article-title":"Establishment of an orthotopic xenograft mice model of retinoblastoma suitable for preclinical testing","volume":"1","author":"Cassoux","year":"2015","journal-title":"Ocul. Oncol. Pathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1038\/nature23465","article-title":"Cdk4\/6 inhibition triggers anti-tumour immunity","volume":"548","author":"Goel","year":"2017","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Donovan, S.L., Schweers, B., Martins, R., Johnson, D., and Dyer, M.A. (2006). Compensation by tumor suppressor genes during retinal development in mice and humans. BMC Biol., 4.","DOI":"10.1186\/1741-7007-4-14"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1101\/gad.1203304","article-title":"Cell type-specific effects of rb deletion in the murine retina","volume":"18","author":"MacPherson","year":"2004","journal-title":"Genes Dev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2952","DOI":"10.1101\/gad.322004","article-title":"Tissue-specific tumor suppressor activity of retinoblastoma gene homologs p107 and p130","volume":"18","author":"Dannenberg","year":"2004","journal-title":"Genes Dev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.canlet.2016.06.012","article-title":"Preclinical platform of retinoblastoma xenografts recapitulating human disease and molecular markers of dissemination","volume":"380","author":"Olaciregui","year":"2016","journal-title":"Cancer Lett."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"E9391","DOI":"10.1073\/pnas.1808903115","article-title":"Developmental stage-specific proliferation and retinoblastoma genesis in rb-deficient human but not mouse cone precursors","volume":"115","author":"Singh","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1172\/JCI88508","article-title":"A mouse model of mycn-driven retinoblastoma reveals mycn-independent tumor reemergence","volume":"127","author":"Wu","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/j.stem.2012.05.009","article-title":"Self-formation of optic cups and storable stratified neural retina from human escs","volume":"10","author":"Nakano","year":"2012","journal-title":"Cell Stem Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"6286","DOI":"10.1038\/ncomms7286","article-title":"Generation of a ciliary margin-like stem cell niche from self-organizing human retinal tissue","volume":"6","author":"Kuwahara","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"eaau6348","DOI":"10.1126\/science.aau6348","article-title":"Thyroid hormone signaling specifies cone subtypes in human retinal organoids","volume":"362","author":"Eldred","year":"2018","journal-title":"Science"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1038\/s41598-017-00774-9","article-title":"Photoreceptor outer segment-like structures in long-term 3d retinas from human pluripotent stem cells","volume":"7","author":"Wahlin","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1056\/NEJMra1803083","article-title":"Retinoblastoma origins and destinations","volume":"390","author":"Cobrinik","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"33628","DOI":"10.1073\/pnas.2011780117","article-title":"Human embryonic stem cell-derived organoid retinoblastoma reveals a cancerous origin","volume":"117","author":"Liu","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4535","DOI":"10.1038\/s41467-021-24781-7","article-title":"Retinoblastoma from human stem cell-derived retinal organoids","volume":"12","author":"Norrie","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1038\/s41389-022-00409-3","article-title":"Mycn induces cell-specific tumorigenic growth in rb1-proficient human retinal organoid and chicken retina models of retinoblastoma","volume":"11","author":"Blixt","year":"2022","journal-title":"Oncogenesis"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e2200721119","DOI":"10.1073\/pnas.2200721119","article-title":"An immature, dedifferentiated, and lineage-deconstrained cone precursor origin of n-myc-initiated retinoblastoma","volume":"119","author":"Singh","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1016\/j.ebiom.2015.06.022","article-title":"Loss of photoreceptorness and gain of genomic alterations in retinoblastoma reveal tumor progression","volume":"2","author":"Kooi","year":"2015","journal-title":"EBioMedicine"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5578","DOI":"10.1038\/s41467-021-25792-0","article-title":"A high-risk retinoblastoma subtype with stemness features, dedifferentiated cone states and neuronal\/ganglion cell gene expression","volume":"12","author":"Liu","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1038\/s42003-024-06596-6","article-title":"A mycn-driven de-differentiation profile identifies a subgroup of aggressive retinoblastoma","volume":"7","author":"Ryl","year":"2024","journal-title":"Commun. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Zugbi, S., Ganiewich, D., Bhattacharyya, A., Aschero, R., Ottaviani, D., Sampor, C., Cafferata, E.G., Mena, M., Sgroi, M., and Winter, U. (2020). Clinical, genomic, and pharmacological study of mycn-amplified rb1 wild-type metastatic retinoblastoma. Cancers, 12.","DOI":"10.3390\/cancers12092714"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.3892\/ol.2015.2857","article-title":"Enhanced sox2 expression in retinoblastoma tissues and peripheral blood is associated with the clinicopathological characteristics of the disease","volume":"9","author":"Tong","year":"2015","journal-title":"Oncol. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"395","DOI":"10.5935\/0004-2749.20160111","article-title":"Immunohistochemical analysis of retinoblastoma cell phenotype using neuronal and glial cell markers","volume":"79","author":"Orellana","year":"2016","journal-title":"Arq. Bras. Oftalmol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.5858\/arpa.2014-0262-OA","article-title":"Expression of angiogenic factors in invasive retinoblastoma tumors is associated with increase in tumor cells expressing stem cell marker sox2","volume":"139","author":"Garcia","year":"2015","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_31","first-page":"dev171686","article-title":"Reproducibility and staging of 3d human retinal organoids across multiple pluripotent stem cell lines","volume":"146","author":"Capowski","year":"2019","journal-title":"Development"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1016\/j.neuron.2017.04.022","article-title":"The dynamic epigenetic landscape of the retina during development, reprogramming, and tumorigenesis","volume":"94","author":"Aldiri","year":"2017","journal-title":"Neuron"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/s41374-021-00573-x","article-title":"Retinoblastoma tumor cell proliferation is negatively associated with an immune gene expression signature and increased immune cells","volume":"101","author":"Sarver","year":"2021","journal-title":"Lab. Investig."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1158\/2159-8290.CD-21-1059","article-title":"Hallmarks of cancer: New dimensions","volume":"12","author":"Hanahan","year":"2022","journal-title":"Cancer Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2240","DOI":"10.1091\/mbc.e11-11-0926","article-title":"Cell survival, DNA damage, and oncogenic transformation after a transient and reversible apoptotic response","volume":"23","author":"Tang","year":"2012","journal-title":"Mol. Biol. Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1038\/s41568-018-0074-8","article-title":"Mtor signalling and cellular metabolism are mutual determinants in cancer","volume":"18","author":"Mossmann","year":"2018","journal-title":"Nat. Rev. Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Kling, M.J., Griggs, C.N., McIntyre, E.M., Alexander, G., Ray, S., Challagundla, K.B., Joshi, S.S., Coulter, D.W., and Chaturvedi, N.K. (2021). Synergistic efficacy of inhibiting mycn and mtor signaling against neuroblastoma. BMC Cancer, 21.","DOI":"10.1186\/s12885-021-08782-9"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"eadj1415","DOI":"10.1126\/science.adj1415","article-title":"Lineage-specific intolerance to oncogenic drivers restricts histological transformation","volume":"383","author":"Gardner","year":"2024","journal-title":"Science"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1186\/s12967-020-02273-4","article-title":"Identification and clinical impact of potentially actionable somatic oncogenic mutations in solid tumor samples","volume":"18","author":"Toomey","year":"2020","journal-title":"J. Transl. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1038\/nature13393","article-title":"Targeting transcription regulation in cancer with a covalent cdk7 inhibitor","volume":"511","author":"Kwiatkowski","year":"2014","journal-title":"Nature"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Joshi, H., Tuli, H.S., Ranjan, A., Chauhan, A., Haque, S., Ramniwas, S., Bhatia, G.K., and Kandari, D. (2023). The pharmacological implications of flavopiridol: An updated overview. Molecules, 28.","DOI":"10.3390\/molecules28227530"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1016\/j.cell.2014.10.024","article-title":"Cdk7 inhibition suppresses super-enhancer-linked oncogenic transcription in mycn-driven cancer","volume":"159","author":"Chipumuro","year":"2014","journal-title":"Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/leu.2014.222","article-title":"Discovery and development of the polo-like kinase inhibitor volasertib in cancer therapy","volume":"29","author":"Gjertsen","year":"2015","journal-title":"Leukemia"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.molcel.2016.09.016","article-title":"Polo-like kinase-1 regulates myc stabilization and activates a feedforward circuit promoting tumor cell survival","volume":"64","author":"Xiao","year":"2016","journal-title":"Mol. Cell"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1016\/j.cell.2009.03.051","article-title":"Retinoblastoma has properties of a cone precursor tumor and depends upon cone-specific mdm2 signaling","volume":"137","author":"Xu","year":"2009","journal-title":"Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1038\/nature13813","article-title":"Rb suppresses human cone-precursor-derived retinoblastoma tumours","volume":"514","author":"Xu","year":"2014","journal-title":"Nature"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1016\/j.it.2020.06.010","article-title":"Organoid models of tumor immunology","volume":"41","author":"Yuki","year":"2020","journal-title":"Trends Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Grebenyuk, S., and Ranga, A. (2019). Engineering organoid vascularization. Front. Bioeng. Biotechnol., 7.","DOI":"10.3389\/fbioe.2019.00039"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1186\/s13046-022-02519-7","article-title":"Patient-specific modeling of stroma-mediated chemoresistance of pancreatic cancer using a three-dimensional organoid-fibroblast co-culture system","volume":"41","author":"Schuth","year":"2022","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e368","DOI":"10.1002\/wdev.368","article-title":"A critical look: Challenges in differentiating human pluripotent stem cells into desired cell types and organoids","volume":"9","author":"Fowler","year":"2020","journal-title":"Wiley Interdiscip. Rev. Dev. Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s40364-022-00356-6","article-title":"Clinical translation of patient-derived tumour organoids- bottlenecks and strategies","volume":"10","author":"Foo","year":"2022","journal-title":"Biomark. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","article-title":"Trimmomatic: A flexible trimmer for illumina sequence data","volume":"30","author":"Bolger","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"Star: Ultrafast universal rna-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1093\/bioinformatics\/btu638","article-title":"Htseq\u2014A python framework to work with high-throughput sequencing data","volume":"31","author":"Anders","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for rna-seq data with deseq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"Clusterprofiler: An R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"Omics J. Integr. Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/17\/8675\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:40:26Z","timestamp":1760035226000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/17\/8675"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,5]]},"references-count":57,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["ijms26178675"],"URL":"https:\/\/doi.org\/10.3390\/ijms26178675","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,5]]}}}