The small extracellular vesicle-mediated intercellular transformation of CXCR1Low to CXCR1High tumour cells promotes the progression of head and neck squamous cell carcinoma

The heterogeneity of tumour cells enables cancers to dynamically adapt to microenvironmental stresses during progression. However, the mechanism underlying the transformation and intercellular communication between heterogeneous tumour cells has remained elusive. Here, we report a "contagion model" that mediates intercellular transformation between heterogeneous tumour cells which facilitates tumour progression. Initially identifying heterogeneous expression of CXCR1, a receptor for interleukin-8, in head and neck squamous cell carcinoma (HNSCC) tumour cells, we found that CXCR1^High tumour cells had higher abilities for migration and invasion. Following interleukin-8-mediated activation, CXCR1^High cells transformed CXCR1^Low cells into CXCR1^High cells through the secretion of small extracellular vesicles (sEVs), which increased the proportion of CXCR1^High cells and facilitated tumour progression. Mechanistically, we demonstrate that sEVs derived from interleukin-8-activated CXCR1^High cells contain high levels of ATP Citrate Lyase (ACLY), which acetylates NF-κB p65 and facilitates its nuclear translocation to transcribe CXCR1 in CXCR1^Low 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 CXCR1^Low to CXCR1^High cells that promotes HNSCC progression. This provides a new paradigm to explain the dynamic changes of heterogeneous tumour cells, and identifies Bempedoic acid as a potential drug for HNSCC treatment.

ATP‐citrate lyase; C‐X‐C motif chemokine receptor 1; head and neck squamous cell carcinoma; heterogeneity; small extracellular vesicles.