{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T21:55:19Z","timestamp":1794002119169,"version":"4.8.0"},"reference-count":27,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,1,17]],"date-time":"2024-01-17T00:00:00Z","timestamp":1705449600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,1,17]],"date-time":"2024-01-17T00:00:00Z","timestamp":1705449600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100003399","name":"Science and Technology Commission of Shanghai Municipality","doi-asserted-by":"publisher","award":["19140901402, 17ZR1423500 and 201409003600"],"award-info":[{"award-number":["19140901402, 17ZR1423500 and 201409003600"]}],"id":[{"id":"10.13039\/501100003399","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003399","name":"Science and Technology Commission of Shanghai Municipality","doi-asserted-by":"publisher","award":["19140901402, 17ZR1423500 and 201409003600"],"award-info":[{"award-number":["19140901402, 17ZR1423500 and 201409003600"]}],"id":[{"id":"10.13039\/501100003399","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82272897"],"award-info":[{"award-number":["82272897"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Commun Signal"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Objectives<\/jats:title>\n                <jats:p>Histological transformation to small cell lung cancer (SCLC) has been identified as a mechanism of TKIs resistance in <jats:italic>EGFR<\/jats:italic>-mutant non-small cell lung cancer (NSCLC). We aim to explore the prevalence of transformation in <jats:italic>EGFR<\/jats:italic>-wildtype NSCLC and the mechanism of SCLC transformation, which are rarely understood.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We reviewed 1474 NSCLC patients to investigate the NSCLC-to-SCLC transformed cases and the basic clinical characteristics, driver gene status and disease course of them. To explore the potential functional genes in SCLC transformation, we obtained pre- and post-transformation specimens and subjected them to a multigene NGS panel involving 416 cancer-related genes. To validate the putative gene function, we established knocked-out models by CRISPR-Cas 9 in HCC827 and A549-TP53<jats:sup>-\/-<\/jats:sup> cells and investigated the effects on tumor growth, drug sensitivity and neuroendocrine phenotype in vitro and in vivo. We also detected the expression level of protein and mRNA to explore the molecular mechanism involved.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We firstly reported an incidence rate of 9.73% (11\/113) of SCLC transformation in <jats:italic>EGFR<\/jats:italic>-wildtype NSCLC and demonstrated that SCLC transformation is irrespective of <jats:italic>EGFR<\/jats:italic> mutation status (<jats:italic>P<\/jats:italic>\u2009=\u20090.16). We sequenced 8 paired tumors and identified a series of mutant genes specially in transformed SCLC such as <jats:italic>SMAD4<\/jats:italic>, <jats:italic>RICTOR<\/jats:italic> and <jats:italic>RET<\/jats:italic>. We firstly demonstrated that <jats:italic>SMAD4<\/jats:italic> deficiency can accelerate SCLC transition by inducing neuroendocrine phenotype regardless of <jats:italic>RB1<\/jats:italic> status in <jats:italic>TP53<\/jats:italic>-deficient NSCLC cells. Further mechanical experiments identified the SMAD4 can regulate <jats:italic>ASCL1<\/jats:italic> transcription competitively with Myc in NSCLC cells and Myc inhibitor acts as a potential subsequent treatment agent.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Transformation to SCLC is irrespective of <jats:italic>EFGR<\/jats:italic> status and can be accelerated by SMAD4 in non-small cell lung cancer. Myc inhibitor acts as a potential therapeutic drug for SMAD4-mediated resistant lung cancer.<\/jats:p>\n                \n              <\/jats:sec>","DOI":"10.1186\/s12964-023-01260-8","type":"journal-article","created":{"date-parts":[[2024,1,17]],"date-time":"2024-01-17T19:02:07Z","timestamp":1705518127000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Transformation to small cell lung cancer is irrespective of EGFR and accelerated by SMAD4-mediated ASCL1 transcription independently of RB1 in non-small cell lung cancer"],"prefix":"10.1186","volume":"22","author":[{"given":"Xi","family":"Ding","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min-xing","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing-xue","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai-xuan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Run-dong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-ping","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai-xing","family":"Ai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,1,17]]},"reference":[{"issue":"4","key":"1260_CR1","doi-asserted-by":"publisher","first-page":"e165","DOI":"10.1016\/S1470-2045(14)71180-5","volume":"16","author":"MG Oser","year":"2015","unstructured":"Oser MG, et al. Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin. Lancet Oncol. 2015;16(4):e165\u201372.","journal-title":"Lancet Oncol"},{"issue":"75","key":"1260_CR2","doi-asserted-by":"publisher","first-page":"75ra26","DOI":"10.1126\/scitranslmed.3002003","volume":"3","author":"LV Sequist","year":"2011","unstructured":"Sequist LV, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3(75):75ra26.","journal-title":"Sci Transl Med"},{"issue":"2","key":"1260_CR3","doi-asserted-by":"publisher","first-page":"a002394","DOI":"10.1101\/mcs.a002394","volume":"4","author":"A Balla","year":"2018","unstructured":"Balla A, et al. Small-cell transformation of ALK-rearranged non-small-cell adenocarcinoma of the lung. 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Mol Ther Oncolytics. 2021;20:470\u201383.","journal-title":"Mol Ther Oncolytics"}],"container-title":["Cell Communication and Signaling"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12964-023-01260-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12964-023-01260-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12964-023-01260-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,17]],"date-time":"2024-01-17T19:02:56Z","timestamp":1705518176000},"score":1,"resource":{"primary":{"URL":"https:\/\/biosignaling.biomedcentral.com\/articles\/10.1186\/s12964-023-01260-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,17]]},"references-count":27,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["1260"],"URL":"https:\/\/doi.org\/10.1186\/s12964-023-01260-8","relation":{},"ISSN":["1478-811X"],"issn-type":[{"value":"1478-811X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,17]]},"assertion":[{"value":"14 January 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 August 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 January 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was conducted under approval of the appropriate Ethics Committees of Shanghai Pulmonary Hospital. All procedures involving human participants were performed in accordance with the ethical standards of the institutional and\/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All animal-involved experiments were carried out with the approval of Tongji University Animal Center.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"45"}}