ITGB6 promotes tumor recurrence and metastasis by mediating the resistance of daughter cells of PGCCs to anoikis

Relapse and metastasis of malignancy remain the primary causes of treatment failure. Our prior research has revealed that polyploid giant cancer cells (PGCCs), these specialized dormant cells, are capable of triggering cancer recurrence and widespread metastasis. Once awakening, these PGCCs give rise to daughter cells (DCs) through asymmetric division, which has been hypothesized as the primary driver of tumor recurrence and metastasis. Nevertheless, the precise role of DCs in head and neck squamous cell carcinoma (HNSCC) remains elusive. In this study, we have elucidated the characteristics of PGCCs and DCs in HNSCC. Furthermore, we have confirmed that the anoikis-resistance of DCs serves as a crucial mechanism for HNSCC recurrence and metastasis following treatment. Utilizing RNA-seq, we discovered that ITGB6 is upregulated in DCs. Additionally, through in vitro and in vivo experiments, we demonstrated that ITGB6 promotes HNSCC metastasis by activating the FAK/PI3K/AKT pathway, thereby inhibiting anoikis in DCs. Taken together, these findings suggest a potential therapeutic approach targeting DCs in HNSCC.