Targeted suppression of SPP1 inhibits tumor invasion and metastasis in NRF2 hyperactivated cisplatin resistant HNSCC

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BACKGROUND: Cisplatin remains the standard systemic therapy for the definitive treatment of head and neck squamous cell carcinoma (HNSCC), however, resistance to cisplatin continues to be a major barrier to effective treatment, particularly in tumors with NRF2 hyperactivation. Recent studies identify secreted phosphoprotein 1 (SPP1/osteopontin) as a key NRF2 target frequently overexpressed in cancers, where it drives aggressive tumor behavior, metastasis, chemoresistance, and, in some cases, immune suppression. Our recent data highlight SPP1 as one of the top 10 NRF2-upregulated genes in cisplatin-resistant HNSCC. However, its specific role in therapy resistance and metastasis in HNSCC remains unclear. Here, we investigate whether targeting SPP1 can suppress tumor aggressiveness and improve cisplatin response in HNSCC. METHODS: Using established human HNSCC cell lines and mouse models, we utilized conventional western blotting, cell invasion, functional proteomics and high resolution spatial transcriptomics to examine the role of SPP1 in driving tumor progression and metastasis in therapy-resistant HNSCC. RESULTS: Targeted suppression of SPP1 improved cisplatin sensitivity, inhibited tumor invasion and metastasis both in vitro and in vivo and reduced expression of several metastatic signaling proteins in NRF2-hyperactivated HNSCC. Proteomic analysis revealed that silencing SPP1 led to dysregulation of critical oncogenic and metastatic signaling pathways, including MAPK, AKT/mTOR, FAK, and PAK1. Spatial transcriptomic analysis uncovered a potential mechanistic interaction between SPP1, integrins and CD44 receptors in both primary and metastatic HNSCC. Spatial annotation and enrichment analyses using HALLMARK revealed gene set signatures of interferon and EMT present in cell clusters with SPP1 expression in both the primary tumor and lung metastases. Finally, increased expression of SPP1 was found to be poor prognostic factor and significantly correlated with NFE2L2/KEAP1 mutational status and higher tumor grade in HNSCC patients. CONCLUSIONS: Targeting dysregulated SPP1 improved cisplatin sensitivity and suppressed tumor invasion and metastasis in NRF2-hyperactivated HNSCC, underscoring the therapeutic potential of SPP1 inhibitors to improve patient outcomes.

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