Stemness and Survival: CD117/CD133 Subpopulations Sustain PI3K Signaling and Drive Imatinib Resistance in Head and Neck Mucosal Melanoma

Authors

• Sofie-Yasmin Hassan, Heinrich-Heine University of Düsseldorf, Duesseldorf, Germany
• Simeon Santourlidis, University Hospital of Duesseldorf, Duesseldorf, Germany
• Thomas W. Flanagan, LSU Health Sciences Center - New OrleansFollow
• Sarah-Lilly Hassan, University of Bonn, Bonn, Germany
• He Zhou, Tulane University, New Orleans, LA
• Morna F. Schmidt, University Hospital RWTH Aachen, Aachen, Germany
• Claudio Cacchi, University Hospital of Aachen, Aachen, Germany
• Matthias Ferdinand Lammert, University Hospital of Aachen, Aachen, Germany
• Mossad Megahed, University Hospital RWTH Aachen, Aachen, Germany
• Amir Sadegh Yazdi, University Hospital RWTH Aachen, Aachen, Germany
• Danny David Jonigk, University Hospital of Aachen, Aachen, Germany
• Marcos J. Araúzo-Bravo, Biogipuzkoa Health Research Institute, San Sebastián, Spain
• Robert T. Brodell, University of Mississippi Medical Center, Jackson, MS
• Sybille Facca, University of Strasbourg, Strasbourg, France
• Youssef Haikel, University of Strasbourg, Strasbourg, France
• Mohamed Hassan, University Hospital RWTH Aachen, Aachen, Germany

Document Type

Article

Publication Date

4-19-2026

Publication Title

Cells

Abstract

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.

First Page

1

Last Page

24

PubMed ID

42041590

Volume

15

Issue

8

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Hassan, Sofie-Yasmin; Santourlidis, Simeon; Flanagan, Thomas W.; Hassan, Sarah-Lilly; Zhou, He; Schmidt, Morna F.; Cacchi, Claudio; Lammert, Matthias Ferdinand; Megahed, Mossad; Yazdi, Amir Sadegh; Jonigk, Danny David; Araúzo-Bravo, Marcos J.; Brodell, Robert T.; Facca, Sybille; Haikel, Youssef; and Hassan, Mohamed, "Stemness and Survival: CD117/CD133 Subpopulations Sustain PI3K Signaling and Drive Imatinib Resistance in Head and Neck Mucosal Melanoma" (2026). School of Medicine Faculty Publications. 4739.
https://digitalscholar.lsuhsc.edu/som_facpubs/4739
10.3390/cells15080721