{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T16:22:45Z","timestamp":1777998165965,"version":"3.51.4"},"reference-count":85,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"918","funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["P30-CA076292"],"award-info":[{"award-number":["P30-CA076292"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006827","name":"Florida Department of Health","doi-asserted-by":"publisher","award":["30-20450-9901"],"award-info":[{"award-number":["30-20450-9901"]}],"id":[{"id":"10.13039\/100006827","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009164","name":"Moffitt Cancer Center","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009164","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NIH\/NCI","award":["R01 CA219347"],"award-info":[{"award-number":["R01 CA219347"]}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Signal."],"published-print":{"date-parts":[[2025,12,23]]},"abstract":"<jats:p>\n                    Cancer-associated fibroblasts (CAFs) are associated with tumor progression and drug resistance. Here, we investigated the mechanisms underlying the cross-talk between CAFs and tumor cells in non\u2013small cell lung cancer (NSCLC). In NSCLC cell lines with\n                    <jats:italic toggle=\"yes\">EML4-ALK<\/jats:italic>\n                    fusions, we observed substantial CAF-mediated drug resistance to clinically used inhibitors of the tyrosine kinase ALK. Array-based cytokine profiling of CAF-derived conditioned medium indicated that a major contributor to the phenomenon was the secreted growth factor HGF, and blocking its receptor MET overcame paracrine resistance to ALK inhibition. However, cell-selective labeling of the proteome in cocultures also revealed an equally important contribution by the fibronectin-integrin pathway, specifically integrin \u03b2\n                    <jats:sub>1<\/jats:sub>\n                    , which was confirmed through pharmacological inhibition and cell-specific silencing or knockout. Concurrent targeting of MET and integrin signaling effectively abrogated ALK inhibitor resistance in\n                    <jats:italic toggle=\"yes\">\n                      EML4-ALK\n                      <jats:sup>+<\/jats:sup>\n                    <\/jats:italic>\n                    NSCLC cells cocultured with CAFs. Moreover, the combination of the ALK inhibitor alectinib with the MET inhibitor capmatinib and\/or the integrin inhibitor cilengitide was more effective than single-agent treatment in suppressing tumor growth in allografted mice. The findings illustrate a previously unappreciated complex nature of concurrent paracrine and juxtacrine mechanisms of CAF-driven resistance that may inform the development of more effective therapeutic approaches.\n                  <\/jats:p>","DOI":"10.1126\/scisignal.ads7662","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T18:58:16Z","timestamp":1766516296000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":3,"title":["Cancer-associated fibroblasts confer ALK inhibitor resistance in\n                    <i>EML4-ALK<\/i>\n                    \u2013driven lung cancer by concurrent integrin and MET signaling"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0310-0296","authenticated-orcid":true,"given":"Qianqian","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA."},{"name":"Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL 33620, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3669-3411","authenticated-orcid":true,"given":"Lily L.","family":"Remsing Rix","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0454-7583","authenticated-orcid":true,"given":"Bina","family":"Desai","sequence":"additional","affiliation":[{"name":"Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL 33620, USA."},{"name":"Department of Tumor Microenvironment and Metastasis, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6425-5000","authenticated-orcid":true,"given":"Daria","family":"Miroshnychenko","sequence":"additional","affiliation":[{"name":"Department of Tumor Microenvironment and Metastasis, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3569-5899","authenticated-orcid":true,"given":"Xueli","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9302-3855","authenticated-orcid":true,"given":"Eric A.","family":"Welsh","sequence":"additional","affiliation":[{"name":"Biostatistics and Bioinformatics Shared Resource, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7636-1318","authenticated-orcid":true,"given":"Bin","family":"Fang","sequence":"additional","affiliation":[{"name":"Proteomics and Metabolomics Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3524-6831","authenticated-orcid":true,"given":"Gabriela M.","family":"Wright","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neelkamal","family":"Chaudhary","sequence":"additional","affiliation":[{"name":"Flow Cytometry Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7783-3439","authenticated-orcid":true,"given":"Jodi L.","family":"Kroeger","sequence":"additional","affiliation":[{"name":"Flow Cytometry Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6728-6857","authenticated-orcid":true,"given":"Robert C.","family":"Doebele","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3818-1762","authenticated-orcid":true,"given":"John M.","family":"Koomen","sequence":"additional","affiliation":[{"name":"Department of Oncologic Sciences, University of South Florida, Tampa, FL 33620, USA."},{"name":"Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3114-1909","authenticated-orcid":true,"given":"Eric B.","family":"Haura","sequence":"additional","affiliation":[{"name":"Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0087-9575","authenticated-orcid":true,"given":"Andriy","family":"Marusyk","sequence":"additional","affiliation":[{"name":"Department of Tumor Microenvironment and Metastasis, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA."},{"name":"Department of Oncologic Sciences, University of South Florida, Tampa, FL 33620, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8242-2770","authenticated-orcid":true,"given":"Uwe","family":"Rix","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA."},{"name":"Department of Oncologic Sciences, University of South Florida, Tampa, FL 33620, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30164-1"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-08-0168"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1097\/JTO.0b013e3181c4dedb"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.gde.2008.01.004"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-13-1610"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-24-0374"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4040"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10690"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.02.027"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature03096"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20140692"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2022.12.003"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00048.2019"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-021-00546-5"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3870"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-12-0237"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature11249"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.03.029"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.abj5879"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-1097"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1311107"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(14)70362-6"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(16)30392-8"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1009472107"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2016.05.025"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-22-3379"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.654940"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1186\/1757-2215-5-34"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature11183"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-11-2972"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-1643"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2021.09.003"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3930"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2529"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.O113.037119"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aap9752"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aaf5011"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-4350"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-17-0109"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1002\/2211-5463.12162"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3003316"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btx415"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.1990.0052"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.matbio.2014.12.001"},{"key":"e_1_3_2_46_2","first-page":"4427","article-title":"CD44 stimulation induces integrin-mediated adhesion of colon cancer cell lines to endothelial cells by up-regulation of integrins and c-Met and activation of integrins","volume":"59","author":"Fujisaki T.","year":"1999","unstructured":"T. Fujisaki, Y. Tanaka, K. Fujii, S. Mine, K. Saito, S. Yamada, U. Yamashita, T. Irimura, S. Eto, CD44 stimulation induces integrin-mediated adhesion of colon cancer cell lines to endothelial cells by up-regulation of integrins and c-Met and activation of integrins. Cancer Res. 59, 4427\u20134434 (1999).","journal-title":"Cancer Res."},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.5461"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.24.19.8586-8599.2004"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2010.532"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.20.22.8513-8525.2000"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)00971-6"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep39805"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm970832g"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature13902"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-09-1001"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2019.01.007"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3205"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc727"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.jbchem.a021283"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2023.12.021"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0096-5"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djac178"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2112"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep46662"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2015.03.008"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-47423-0"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-0569"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1420785112"},{"key":"e_1_3_2_69_2","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.202200766"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2023.09.011"},{"key":"e_1_3_2_71_2","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.2489"},{"key":"e_1_3_2_72_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11942"},{"key":"e_1_3_2_73_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1701821114"},{"key":"e_1_3_2_74_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2020.02.003"},{"key":"e_1_3_2_75_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-3492"},{"key":"e_1_3_2_76_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3667"},{"key":"e_1_3_2_77_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.lungcan.2022.07.010"},{"key":"e_1_3_2_78_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-016-2162-z"},{"key":"e_1_3_2_79_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0006529"},{"key":"e_1_3_2_80_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.01.014"},{"key":"e_1_3_2_81_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2018.02.011"},{"key":"e_1_3_2_82_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3438"},{"key":"e_1_3_2_83_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-14-153"},{"key":"e_1_3_2_84_2","doi-asserted-by":"publisher","DOI":"10.1017\/S1431927621012393"},{"key":"e_1_3_2_85_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaw8412"},{"key":"e_1_3_2_86_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab1038"}],"container-title":["Science Signaling"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scisignal.ads7662","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T18:58:21Z","timestamp":1766516301000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scisignal.ads7662"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,23]]},"references-count":85,"journal-issue":{"issue":"918","published-print":{"date-parts":[[2025,12,23]]}},"alternative-id":["10.1126\/scisignal.ads7662"],"URL":"https:\/\/doi.org\/10.1126\/scisignal.ads7662","relation":{},"ISSN":["1945-0877","1937-9145"],"issn-type":[{"value":"1945-0877","type":"print"},{"value":"1937-9145","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,23]]},"assertion":[{"value":"2024-08-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-13","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-28","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eads7662"}}