The Small Extracellular Vesicle-Mediated Intercellular Transformation of CXCR1Low to CXCR1High Tumor Cells Promotes the Progression of Head and Neck Squamous Cell Carcinoma

The heterogeneity of tumor cells enables cancers to dynamically adapt to microenvironmental stresses during progression. However, the mechanism underlying the transformation and intercellular communication between heterogeneous tumor cells has remained elusive. Here, we report a “contagion model” that mediates intercellular transformation between heterogeneous tumor cells which facilitates tumor progression. Initially identifying heterogeneous expression of CXCR1, a receptor for interleukin-8, in head and neck squamous cell carcinoma (HNSCC) tumor cells. Following interleukin-8-mediated activation, CXCR1High cells transformed CXCR1Low cells into CXCR1High cells through the secretion of small extracellular vesicles (sEVs), which increased the proportion of CXCR1High cells and facilitated tumor progression. Mechanistically, we demonstrate that sEVs derived from interleukin-8-activated CXCR1High cells contain high levels of ATP citrate lyase (ACLY), which acetylates NF-κB p65 and facilitates its nuclear translocation to transcribe CXCR1 in CXCR1Low cells. That process could be inhibited by Bempedoic acid, an FDA-approved ACLY-targeted drug. Taken together, our study reveals an sEV-mediated transformation of CXCR1Low to CXCR1High cells that promotes HNSCC progression. This provides a new paradigm to explain the dynamic changes of heterogeneous tumor cells, and identifies Bempedoic acid as a potential drug for HNSCC treatment. To investigated the function of IL-8 to HNSCC cell with different CXCR1 expression, we used recombinant human IL-8 to stimulated HN4, HN6 and Cal27 cells. To investigated the downstream of ACLY, we overexpressed ACLY in HN4, HN6 and Cal27 cells.