{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T05:19:51Z","timestamp":1765430391015,"version":"3.46.0"},"reference-count":85,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T00:00:00Z","timestamp":1765152000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["19-74-30011"],"award-info":[{"award-number":["19-74-30011"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Russian state-funded project for ICBFM SB RAS","award":["125012300659-6","125012300660-2"],"award-info":[{"award-number":["125012300659-6","125012300660-2"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>A disintegrin and metalloproteinase with thrombospondin motifs 6 (ADAMTS6) is an extracellular matrix (ECM) protease that promotes the invasion of lung adenocarcinoma (LUAD) cells. Herein, we investigate its role in epithelial-mesenchymal transition (EMT), a process that drives metastasis and drug resistance in LUAD. Re-analysis of microarray and RNA sequencing data from LUAD cells revealed that during EMT, TGF-\u03b21 increased ADAMTS6 expression, presumably through the SMAD pathway, as SMAD2 loss completely blocked this effect. Moreover, ADAMTS6 was shown to occupy hub positions within TGF-\u03b21-associated gene networks. Using additional datasets, we found that ADAMTS6 expression increased under other EMT-inducing conditions, including IL-1\u03b2 induction and acquired gefitinib resistance, but decreased upon knockdown of Twist1, a master regulator of EMT. Knockout of ADAMTS6 repressed colony formation, migration, invasion, and doxorubicin resistance but enhanced cell\u2013ECM adhesion in A549 cells. This effect was mediated by EMT inhibition, evidenced by upregulation of E-cadherin and downregulation of N-cadherin, vimentin, and Twist1, and was accompanied by suppressed nuclear translocation of the NF-\u03baB p65 subunit. Re-analysis of transcriptomic data from patient tumors demonstrated that high ADAMTS6 expression correlated with the expression of EMT markers, further supporting the ADAMTS6\u2013EMT link. Moreover, high ADAMTS6 expression was associated with worse survival prognosis. Overall, ADAMTS6 promotes EMT in LUAD cells and may be considered a marker of this process, as well as a potential therapeutic target for its inhibition.<\/jats:p>","DOI":"10.3390\/ijms262411850","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T14:52:24Z","timestamp":1765205544000},"page":"11850","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Deciphering the Role of ADAMTS6 in the Epithelial\u2013Mesenchymal Transition of Lung Adenocarcinoma Cells"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1092-0014","authenticated-orcid":false,"given":"Kirill V.","family":"Odarenko","sequence":"first","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anastasiya M.","family":"Matveeva","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3393-3192","authenticated-orcid":false,"given":"Grigory A.","family":"Stepanov","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4044-1049","authenticated-orcid":false,"given":"Marina A.","family":"Zenkova","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7569-9555","authenticated-orcid":false,"given":"Andrey V.","family":"Markov","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,8]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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