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-?B 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. Overall design: 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.

肿瘤细胞的异质性使得癌症在进展过程中可动态适应微环境压力。然而，异质性肿瘤细胞之间的表型转化及细胞间通信的潜在机制仍不明晰。本研究报道了一种“传染模型”，该模型可介导异质性肿瘤细胞间的表型转化，进而促进肿瘤进展。本研究首先在头颈部鳞状细胞癌（head and neck squamous cell carcinoma, HNSCC）肿瘤细胞中鉴定出白细胞介素-8（interleukin-8, IL-8）的受体——CXC趋化因子受体1（CXCR1）——的异质性表达。在白细胞介素-8介导的激活后，CXCR1高表达（CXCR1High）细胞通过分泌小细胞外囊泡（small extracellular vesicles, sEVs）将CXCR1低表达（CXCR1Low）细胞转化为CXCR1High细胞，这一过程提升了CXCR1High细胞的比例，进而促进肿瘤进展。机制研究表明，经白细胞介素-8激活的CXCR1High细胞所分泌的小细胞外囊泡富含ATP柠檬酸裂解酶（ATP citrate lyase, ACLY），该酶可乙酰化核因子-κB p65（NF-κB p65），并促进其核转位，从而在CXCR1Low细胞中转录CXCR1。这一过程可被贝匹多酸（Bempedoic acid）——一种经美国食品药品监督管理局（FDA）批准的ACLY靶向药物——所抑制。综上，本研究揭示了一种由小细胞外囊泡介导的、将CXCR1Low细胞转化为CXCR1High细胞的机制，该机制可促进头颈部鳞状细胞癌进展。这为解释异质性肿瘤细胞的动态变化提供了全新范式，并确定贝匹多酸可作为头颈部鳞状细胞癌治疗的潜在药物。整体实验设计：为探究白细胞介素-8对不同CXCR1表达水平的头颈部鳞状细胞癌细胞的功能影响，我们使用重组人白细胞介素-8刺激HN4、HN6及Cal27细胞。为探究ACLY的下游调控通路，我们在HN4、HN6及Cal27细胞中过表达ACLY。