{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T09:02:34Z","timestamp":1776934954966,"version":"3.51.2"},"reference-count":75,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T00:00:00Z","timestamp":1776556800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Head and neck mucosal melanoma (HNMM) arises in the nasal and oral cavities and has the propensity to metastasize to local and distant body sites. HNMM is also notable for its resistance to available therapeutics. The rarity of this disease makes it difficult to conduct large-scale clinical studies to develop standard treatment protocols. In contrast to cutaneous melanoma, c-Kit-dependent pathways are well studied in HNNMM and provide a potential therapeutic target. We identified and isolated genetically distinct subpopulations with stem cell characteristics in HNMM samples bearing Kit wild-type and mutations. Functional analysis of these subpopulations reveals that, in addition to expressing the stem cell marker proteins CD20, CD117, CD133, and CD166, these subpopulations are characterized by self-renewal potential, migratory capacity, and resistance to Kit inhibitors such as Imatinib. Immunofluorescence staining and inhibition experiments demonstrate that the maintenance and resistance of HHMM subpopulations to Kit inhibitors is mediated by the Kit signal to the PI3K signaling pathway. The KIT signal to the PI3K signaling pathway does not result exclusively from a KIT mutation localized to Exon 17, but can also be triggered by mutations localized to Exons 11 and 13. In the present study, we identify and characterize an HNMM subpopulation with stemness properties in patients with c-Kit wild-type and mutation, and demonstrate for the first time the mechanisms by which the CD117+\/CD133+ HNMM subpopulations survive and confer resistance to the specific inhibitor of c-Kit mutation.<\/jats:p>","DOI":"10.3390\/cells15080721","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T12:01:22Z","timestamp":1776686482000},"page":"721","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Stemness and Survival: CD117+\/CD133+ Subpopulations Sustain PI3K Signaling and Drive Imatinib Resistance in Head and Neck Mucosal Melanoma"],"prefix":"10.3390","volume":"15","author":[{"given":"Sofie-Yasmin","family":"Hassan","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Faculty of Mathematics and Natural Science, Heinrich-Heine University of D\u00fcsseldorf, University Street 1, 40225 Duesseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0743-5336","authenticated-orcid":false,"given":"Simeon","family":"Santourlidis","sequence":"additional","affiliation":[{"name":"Institute for Transplantation Diagnostics and Cell Therapeutics, University Hospital of Duesseldorf, 40225 Duesseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas W.","family":"Flanagan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Therapeutics, LSU Health Sciences Center, New Orleans, LA 70112, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah-Lilly","family":"Hassan","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5043-5334","authenticated-orcid":false,"given":"He","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, School Medicine, Tulane University, New Orleans, LA 70112, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Morna F.","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Allergology, University Hospital RWTH Aachen, 52074 Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudio","family":"Cacchi","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital of Aachen, 52074 Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias Ferdinand","family":"Lammert","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital of Aachen, 52074 Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mossad","family":"Megahed","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Allergology, University Hospital RWTH Aachen, 52074 Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amir Sadegh","family":"Yazdi","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Allergology, University Hospital RWTH Aachen, 52074 Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Danny David","family":"Jonigk","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital of Aachen, 52074 Aachen, Germany"},{"name":"German Center for Lung Research, BREATH Hanover, 30625 Hanover, Germany"},{"name":"Center for Integrated Oncology Aachen Bonn Cologne D\u00fcsseldorf (CIO ABCD), 52074 Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3264-464X","authenticated-orcid":false,"given":"Marcos J.","family":"Ara\u00fazo-Bravo","sequence":"additional","affiliation":[{"name":"Group of Computational Biology and Systems Biomedicine, Biogipuzkoa Health Research Institute, 20014 San Sebasti\u00e1n, Spain"},{"name":"Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain"},{"name":"Department of Cell Biology and Histology, Faculty of Medicine and Nursing, University of Basque Country (UPV\/EHU), 48940 Leioa, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert T.","family":"Brodell","sequence":"additional","affiliation":[{"name":"Department of Pathology and Dermatology, University of Mississippi Medical Center, 2500 North Sae Street, Jackson, MS 39216, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sybille","family":"Facca","sequence":"additional","affiliation":[{"name":"ICube CNRS UMR7357, University of Strasbourg, 67000 Strasbourg, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4469-0360","authenticated-orcid":false,"given":"Youssef","family":"Haikel","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, University of Strasbourg, 67000 Strasbourg, France"},{"name":"Department of Operative Dentistry and Endodontics, Dental Faculty, University of Strasbourg, 67000 Strasbourg, France"},{"name":"P\u00f4le de M\u00e9decine et Chirurgie Bucco-Dentaire, H\u00f4pital Civil, H\u00f4pitaux Universitaire de Strasbourg, 67000 Strasbourg, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0336-6425","authenticated-orcid":false,"given":"Mohamed","family":"Hassan","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Allergology, University Hospital RWTH Aachen, 52074 Aachen, Germany"},{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, University of Strasbourg, 67000 Strasbourg, France"},{"name":"Department of Operative Dentistry and Endodontics, Dental Faculty, University of Strasbourg, 67000 Strasbourg, France"},{"name":"Research Laboratory of Surgery-Oncology, Department of Surgery, Tulane University School of Medicine, New Orleans, LA 70112, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1002\/cncr.20866","article-title":"Incidence of noncutaneous 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