Targeting MDA-9/syntenin-1 (SDCBP) as a strategy to eliminate head and neck squamous cell carcinoma stem cells.

Melanoma differentiation associated gene-9 (MDA-9), also known as Syntenin-1 or SDCBP, exhibits elevated expression in multiple cancers, promoting invasion, migration, and tumor cell survival. The TCGA database reveals high MDA-9 expression in late-stage HPV (-) HNSCC tissues, which associates with poor patient survival. Moreover, bioinformatics analyses support a potential role of MDA-9 in promoting cancer stemness in HNSCC tissues. We characterized the functional role of MDA-9 in HNSCC tumorigenesis, particularly in relation to cancer stem cell maintenance. Knockdown of MDA-9 suppresses BMI1, a functional cancer stem cell marker in HNSCC, and the self-renewal of cultured HNSCC cells. Mechanistically, MDA-9 controls expression of BMI1 through NF-κB p65. Targeting MDA-9 with a specific small molecule pharmacological inhibitor, IVMT-Rx-4, inhibits HNSCC growth and metastasis in a HNSCC xenograft mouse model. In vivo lineage tracing reveals that IVMT-Rx-4 potently inhibits self-renewal and tumorigenicity of Bmi1+ cancer stem cells in a spontaneous model of HNSCC. Additionally, IVMT-Rx-4 significantly improves treatment with cisplatin by eliminating cisplatin-enriched Bmi1+ cancer stem cells, thereby overcoming cisplatin resistance. Taken together, our results demonstrate that targeting MDA-9 with IVMT-Rx-4 is an effective strategy for treating HNSCC by eliminating cancer stem cells, and IVMT-Rx-4 is a promising chemical entity that may be amenable for developing an effective therapy for HNSCC.