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Given the role of cancer stem cells (CSCs) in cancer recurrence and drug resistance, we aimed to identify CSC subpopulations within two MTC cell lines harboring pathogenic variants in the two most common MEN2-associated codons. We analyzed 15 stemness-associated markers, along with well-established thyroid stem cell markers (CD133, CD44, and ALDH1), a novel candidate (DLK1), and multidrug resistance proteins (MRP1 and MRP3). The ability to efflux the fluorescent dye Hoechst 3342 and form spheroids, representing CSC behavior, was also assessed. MZ-CRC-1 cells (p.M918T) displayed higher expressions of canonical markers, DLK1, and MRP proteins than TT cells (p.C634W). MZ-CRC-1 cells also formed more spheroids and showed less dye accumulation (p &lt; 0.0001). Finally, we observed that DLK1+ cells (those expressing DLK1) in both cell lines exhibited significantly higher levels of stemness markers compared to DLK1\u2212 cells (those lacking DLK1 expression). These findings underscore DLK1\u2019s role in enhancing the stemness phenotype, providing valuable insights into MTC progression and resistance and suggesting potential therapeutic implications.<\/jats:p>","DOI":"10.3390\/ijms252211924","type":"journal-article","created":{"date-parts":[[2024,11,6]],"date-time":"2024-11-06T06:27:39Z","timestamp":1730874459000},"page":"11924","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["DLK1 Is Associated with Stemness Phenotype in Medullary Thyroid Carcinoma Cell Lines"],"prefix":"10.3390","volume":"25","author":[{"given":"Danilo Dias","family":"da Silva","sequence":"first","affiliation":[{"name":"Genetic Bases of Thyroid Tumour Laboratory, Division of Genetics, Department of Morphology and Genetics, Escola Paulista de Medicina, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo 04039-032, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8288-2577","authenticated-orcid":false,"given":"Rodrigo Pinheiro","family":"Araldi","sequence":"additional","affiliation":[{"name":"Genetic Bases of Thyroid Tumour Laboratory, Division of Genetics, Department of Morphology and Genetics, Escola Paulista de Medicina, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo 04039-032, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5518-2647","authenticated-orcid":false,"given":"Mariana Rocha","family":"Belizario","sequence":"additional","affiliation":[{"name":"Genetic Bases of Thyroid Tumour Laboratory, Division of Genetics, Department of Morphology and Genetics, Escola Paulista de Medicina, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo 04039-032, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Welbert Gomes","family":"Rocha","sequence":"additional","affiliation":[{"name":"Genetic Bases of Thyroid Tumour Laboratory, Division of Genetics, Department of Morphology and Genetics, Escola Paulista de Medicina, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo 04039-032, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6123-6098","authenticated-orcid":false,"given":"Rui Monteiro de Barros","family":"Maciel","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Endocrinologia Molecular e Translacional, Disciplina de Endocrinologia e Metabologia, Departamento de Medicina, Escola Paulista de Medicina, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo 04039-032, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0156-8274","authenticated-orcid":false,"given":"Janete Maria","family":"Cerutti","sequence":"additional","affiliation":[{"name":"Genetic Bases of Thyroid Tumour Laboratory, Division of Genetics, Department of Morphology and Genetics, Escola Paulista de Medicina, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo 04039-032, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"American Thyroid Association Guidelines Task Force, Kloos, R.T., Eng, C., Evans, D.B., Francis, G.L., Gagel, R.F., Gharib, H., Moley, J.F., Pacini, F., and Ringel, M.D. (2009). 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