{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T08:49:28Z","timestamp":1791967768201,"version":"4.3.4"},"reference-count":56,"publisher":"National Academy of Sciences","issue":"37","license":[{"start":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T00:00:00Z","timestamp":1757462400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS-2025-00557242"],"award-info":[{"award-number":["RS-2025-00557242"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS-2024-00334460"],"award-info":[{"award-number":["RS-2024-00334460"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS-2023-00225574"],"award-info":[{"award-number":["RS-2023-00225574"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007107","name":"Korea Advanced Institute of Science and Technology","doi-asserted-by":"publisher","award":["N11240028"],"award-info":[{"award-number":["N11240028"]}],"id":[{"id":"10.13039\/501100007107","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS-2024-00407383"],"award-info":[{"award-number":["RS-2024-00407383"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,9,16]]},"abstract":"<jats:p>Microscopic examination of biopsy tissues remains essential for cancer diagnosis, despite advancements in sequencing technologies. Alterations in nuclear size or the nuclear-to-cytoplasmic ratio are hallmark features of cancer cells and often correlate with disease progression. However, the mechanisms underlying nuclear size abnormalities and their impact on tumor progression remain unclear. In this study, we demonstrate that nuclear hypertrophy occurs in response to enhanced DNA replication stress, a key characteristic of cancer cells. Increased actin polymerization within the nucleus appears to be the primary mechanism driving nuclear hypertrophy downstream of the ATR-CHEK1 pathway. Replication stress\u2013induced nuclear hypertrophy alters transcriptomic profiles and chromatin topology, while reducing the migratory and metastatic capacity of cancer cells. In addition, nuclear hypertrophy in cancer cells is associated with increased infiltration of antitumor immune cells. Our findings suggest that cell-autonomous effects of nuclear hypertrophy do not promote cellular fitness or aggressive characteristics in cancer cells. This may explain why cells with nuclear hypertrophy are not positively selected and persist as a subpopulation during tumor progression and metastasis. Furthermore, the link between replication stress and nuclear hypertrophy provides insights into why enlarged nuclei are consistently observed in advanced-stage cancers.<\/jats:p>","DOI":"10.1073\/pnas.2424709122","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T15:51:41Z","timestamp":1757519501000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":4,"title":["Replication stress\u2013induced nuclear hypertrophy alters chromatin topology and impacts cancer cell fitness"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5759-727X","authenticated-orcid":false,"given":"Changgon","family":"Kim","sequence":"first","affiliation":[{"name":"Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology","place":["Daejeon, Republic of Korea"]},{"name":"Division of Hematology and Oncology, Department of Internal Medicine, Korea University College of Medicine","place":["Seoul, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Semyeong","family":"Hong","sequence":"additional","affiliation":[{"name":"Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology","place":["Daejeon, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soo Hyeon","family":"Ma","sequence":"additional","affiliation":[{"name":"Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology","place":["Daejeon, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5906-8604","authenticated-orcid":false,"given":"Joochan","family":"Lee","sequence":"additional","affiliation":[{"name":"Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology","place":["Daejeon, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hee","family":"So","sequence":"additional","affiliation":[{"name":"Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology","place":["Daejeon, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun Young","family":"Kim","sequence":"additional","affiliation":[{"name":"Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology","place":["Daejeon, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eunbie","family":"Shin","sequence":"additional","affiliation":[{"name":"Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology","place":["Daejeon, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kippeum","family":"Lee","sequence":"additional","affiliation":[{"name":"Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology","place":["Daejeon, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sohee","family":"Choi","sequence":"additional","affiliation":[{"name":"Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology","place":["Daejeon, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juyeon","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Physics, Korea Advanced Institute of Science and Technology","place":["Daejeon, Republic of Korea"]},{"name":"Korea Advanced Institute of Science and Technology Institute for Health Science and Technology","place":["Daejeon, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0528-6661","authenticated-orcid":false,"given":"YongKeun","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Physics, Korea Advanced Institute of Science and Technology","place":["Daejeon, Republic of Korea"]},{"name":"Korea Advanced Institute of Science and Technology Institute for Health Science and Technology","place":["Daejeon, Republic of Korea"]},{"name":"Tomocube Inc.","place":["Daejeon, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8780-704X","authenticated-orcid":false,"given":"You-Me","family":"Kim","sequence":"additional","affiliation":[{"name":"Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology","place":["Daejeon, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Hun","family":"Kim","sequence":"additional","affiliation":[{"name":"Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology","place":["Daejeon, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9379-3243","authenticated-orcid":false,"given":"Joon","family":"Kim","sequence":"additional","affiliation":[{"name":"Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology","place":["Daejeon, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,9,10]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1159\/000508780"},{"key":"e_1_3_4_2_2","first-page":"1271","article-title":"Prognostic relevance of three histological grading methods in breast cancer","volume":"19","author":"Latinovic L.","year":"2001","unstructured":"L. Latinovic , Prognostic relevance of three histological grading methods in breast cancer. Int. J. Oncol. 19, 1271\u20131277 (2001).","journal-title":"Int. J. Oncol."},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-031-06573-6_16"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1111\/his.13380"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63468-2"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2012.11.004"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.4161\/nucl.2.2.15446"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10577-021-09664-3"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200708054"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.76075"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.09.012"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2897"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-37341-y"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2014.04.035"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0266645"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-012414-040424"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1915387117"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/iyad031"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/75556"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1002\/pro.4218"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3790"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.3390\/biom7010019"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-4827(76)90336-0"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-380888-2.00003-0"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81209-X"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-43183-5"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2026"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.3390\/genes14020272"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2016.01.011"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.29455"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.2c00004"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-022-02420-9"},{"key":"e_1_3_4_34_2","first-page":"773","article-title":"Metastasis: Quantitative analysis of distribution and fate of tumor emboli labeled with 125I-5-iodo-2\u2032 -deoxyuridine","volume":"45","author":"Fidler I. J.","year":"1970","unstructured":"I. J. Fidler, Metastasis: Quantitative analysis of distribution and fate of tumor emboli labeled with 125I-5-iodo-2\u2032 -deoxyuridine. JNCI J. Natl. Cancer Inst. 45, 773\u2013782 (1970).","journal-title":"JNCI J. Natl. Cancer Inst."},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.15419\/bmrat.v9i10.774"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1111\/febs.14377"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1097\/CMR.0b013e3283543d72"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2011.300"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2019.08.002"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-020-01048-4"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-018-0063-5"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1364\/OE.412510"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.5483\/BMBRep.2023-0249"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04803-0"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.11.019"},{"key":"e_1_3_4_47_2","doi-asserted-by":"crossref","unstructured":"C. Van Rechem Data from \u201cCollective regulation of chromatin modifications predicts replication timing during cell cycle.\u201d Cell Rep. 37 109799 (2021).","DOI":"10.1016\/j.celrep.2021.109799"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2022.03.009"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20047-w"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-29925-x"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-020-00605-6"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1529\/biophysj.108.132274"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1080\/19491034.2020.1806661"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1186\/s11658-024-00591-9"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15092653"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-023-01280-4"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2424709122","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T15:52:17Z","timestamp":1757519537000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2424709122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,10]]},"references-count":56,"journal-issue":{"issue":"37","published-print":{"date-parts":[[2025,9,16]]}},"alternative-id":["10.1073\/pnas.2424709122"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2424709122","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,10]]},"assertion":[{"value":"2024-12-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-31","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-10","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2424709122"}}