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In contrast, patients diagnosed with lung squamous cell carcinoma (LUSC) suffer worse survival outcomes and lack effective targeted treatment options. Identification of molecular drivers of LUSC to support development of targeted treatments is urgently needed. Addressing this need, the current report introduces the novel cancer gene SLIT- and NTRK-like family member 3 (SLITRK3) and its role in activating the neurotrophic receptor tyrosine kinase 3 (NTRK3) in LUSC cells. Multiple genome-wide data sets from patient samples were produced by us or downloaded from public databases to analyze tumor gene copy number aberrations, mRNA expression and associated survival outcomes. An accompanying mechanistic study employed LUSC cell lines and multiple methods, including in situ immunofluorescence, sphere-formation assay, and fluorescence-activated cell sorting analysis of the CD133-positive cell fraction. Altogether, the results indicate that gene amplification and consequent high expression of SLITRK3 in LUSC is associated with worse outcomes and induces SLITRK3-dependent activation of NTRK3 to promote a cancer stem cell phenotype that is inhibited by existing NTRK-targeted inhibitors. Based on a recent literature search, this is the first report of a mechanistic role for SLITRK3 in cancer.<\/jats:p>","DOI":"10.1186\/s43556-021-00051-2","type":"journal-article","created":{"date-parts":[[2021,8,30]],"date-time":"2021-08-30T03:28:37Z","timestamp":1630294117000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Role of novel cancer gene SLITRK3 to activate NTRK3 in squamous cell lung cancer"],"prefix":"10.1186","volume":"2","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4832-9457","authenticated-orcid":false,"given":"Aliccia","family":"Bollig-Fischer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Bao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morenci","family":"Manning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greg","family":"Dyson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon K.","family":"Michelhaugh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandeep","family":"Mittal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerold","family":"Bepler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirva","family":"Mamdani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,8,30]]},"reference":[{"key":"51_CR1","unstructured":"American cancer society. 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Nucleic Acids Res. 2012;40(Database issue):D1144\u20139 https:\/\/doi.org\/10.1093\/nar\/gkr1013.","journal-title":"Nucleic Acids Res"}],"container-title":["Molecular Biomedicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s43556-021-00051-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s43556-021-00051-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s43556-021-00051-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,30]],"date-time":"2021-08-30T04:13:05Z","timestamp":1630296785000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s43556-021-00051-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,30]]},"references-count":48,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["51"],"URL":"https:\/\/doi.org\/10.1186\/s43556-021-00051-2","relation":{},"ISSN":["2662-8651"],"issn-type":[{"value":"2662-8651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,30]]},"assertion":[{"value":"13 April 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 August 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 August 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The research using human tumor specimens was pre-approved by the Wayne State University Institutional Review Board (IRB). Publicly available, existing human data sets were collected from approved online databases including the U.S. National Center for Biotechnology Information Gene Expression Omnibus and U.S. National Cancer Institute TCGA program.Written informed consent was obtained from all donating patients and methods conformed to the standards set by the Declaration of Helsinki.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no conflicts interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"26"}}