癌相关成纤维细胞分泌ADM激活AKT-mTOR通路促进糖酵解维持肿瘤细胞干性引起鼻咽癌放疗抵抗及其机制研究

Nasopharyngeal carcinoma (NPC) is one of the most common malignant tumors in southern China. Radiotherapy is the first-line choice for NPC, while radioresistance is the main reason that restricts the efficacy and prognosis. Our previous study indicated that the content of cancer-associated fibroblasts (CAFs) is related to the poor survival of NPC patients. Co-culture of primary CAFs and nasopharyngeal carcinoma cells promotes radioresistance. The role and molecular mechanism of CAFs in radioresistance of NPC is still elusive..Using transcriptome sequencing and LC-MS/MS, we found that ADM may be an important molecule from CAFs deliver to NPC cells causing raidoresistance. First, we detected the expression of ADM in NPC tissues is associated with poor survival, and our experiment initially verified the effect of ADM on the sensitivity of radiotherapy in NPC cells. Further investigation by sphere formation and side population analysis found that the increase in cell stemness is the main reason for ADM-mediated resistance to radiotherapy. Then, we used GSEA pathway enrichment to find that ADM may promote cell glycolysis and maintain cell stemness through the AKT-mTOR pathway. Our project will clarify CAFs-derived ADM-mediated changes in cell metabolism and radioresistance of NPC cells due to increased NPC cell stemness and related mechanisms. Furthermore, our study provides new targets for the improvement of radiotherapy sensitization and clinical prognosis in NPC.

鼻咽癌（NPC）是我国南部最常见的恶性肿瘤之一，放疗为NPC根治手段，而放疗抵抗是制约NPC疗效和预后的瓶颈。我们前期发现：鼻咽癌相关成纤维细胞（CAFs）与患者不良预后相关，且原代CAFs与NPC细胞共培养可促进NPC细胞放疗抵抗。CAFs在鼻咽癌放疗抵抗中的作用及分子机制尚不明确。.本项目通过CAFs转录组测序及上清蛋白质谱筛选发现ADM可能为CAFs递送的关键分子。首先，我们检测了鼻咽癌组织中ADM的表达水平，初步验证ADM对鼻咽癌放疗敏感性的影响及与患者不良预后的相关性。进一步通过成球实验、侧群分析等实验证明细胞干性增加是ADM介导放疗抵抗的主要原因。继而运用通路富集发现ADM可能通过AKT-mTOR通路促进糖酵解维持肿瘤细胞干性。本项目将阐明CAFs来源的ADM介导细胞代谢改变、细胞干性增加导致的NPC放疗抵抗及相关机制，进一步为NPC放疗增敏及预后改善提供新的靶标。

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