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However, the identification of such a population in non-small cell lung carcinoma (NSCLC) has been hindered by the lacking of reliable surface markers, and very few of the currently available surface markers are of functional significance. Here, we demonstrate that a subpopulation of TICs could be specifically defined by the voltage-gated calcium channel \u03b12\u03b41 subunit from non-small cell lung carcinoma (NSCLC) cell lines and clinical specimens. The \u03b12\u03b41<jats:sup>+<\/jats:sup> NSCLC TICs are refractory to conventional chemotherapy, and own stem cell-like properties such as self-renewal, and the ability to generate heterogeneous tumors in NOD\/SCID mice. Moreover, \u03b12\u03b41<jats:sup>+<\/jats:sup> NSCLC cells are more enriched for TICs than CD133<jats:sup>+<\/jats:sup>, or CD166<jats:sup>+<\/jats:sup> cells. Interestingly, \u03b12\u03b41 is functionally sufficient and indispensable to promote TIC properties by mediating Ca<jats:sup>2+<\/jats:sup> influx into cells, which subsequently activate Calcineurin\/NFATc2 signaling that directly activates the expression of <jats:italic>NOTCH3<\/jats:italic>, <jats:italic>ABCG2<\/jats:italic>. Importantly, a specific antibody against \u03b12\u03b41 has remarkably therapeutic effects on NSCLC xenografts by eradicating TICs. Hence, targeting \u03b12\u03b41 to prevent calcium influx provides a novel strategy for targeted therapy against TICs of NSCLC.<\/jats:p>","DOI":"10.1038\/s41419-021-03522-0","type":"journal-article","created":{"date-parts":[[2021,3,11]],"date-time":"2021-03-11T13:03:15Z","timestamp":1615467795000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Calcium channel \u03b12\u03b41 subunit is a functional marker and therapeutic target for tumor-initiating cells in non-small cell lung cancer"],"prefix":"10.1038","volume":"12","author":[{"given":"Yuanyuan","family":"Ma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6732-9466","authenticated-orcid":false,"given":"Wei","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0289-2885","authenticated-orcid":false,"given":"Zhiqian","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,11]]},"reference":[{"key":"3522_CR1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21442","volume":"68","author":"RL Siegel","year":"2018","unstructured":"Siegel, R. 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