流行病学数据显示，吸烟是胰腺癌（PDAC）的重要诱发因素，但其机制尚不明确。胰腺癌早期事件始发于腺泡-导管化生（ADM），课题组前期发现烟草中主要致癌物NNK明显促进动物胰腺ADM和PanIN发生，并伴随LncRNA LINC00857-Wnt/β-catenin通路异常激活。因此我们推测：NNK激活腺泡细胞LncRNA LINC00857-Wnt/β-catenin通路，促使腺泡细胞“重编程”，启动ADM–PanIN–PDAC的连续性恶性转化，最终导致胰腺癌发生。为证实该假说，我们从临床病理、体外细胞、转基因动物三个层次，采用激光共聚焦、分子生物学、3D细胞培养、细胞谱系示踪、质谱分析、小动物成像等技术，解析NNK诱发胰腺ADM的作用方式，探究LINC00857-Wnt/β-catenin通路在NNK诱导胰腺恶性转化中的作用，从而阐明吸烟和胰腺癌发生的具体机制，为胰腺癌防治提供新的思路。

Epidemiological data showed that smoking is one of the most important risk factor which causes pancreatic ductal adenocarcinoma (PDAC), but the underlying mechanism remains unclear. Acinar-ductal metaplasia (ADM) as an early precancerous pathological change emerges before PanIN, and correlate with the activation of Wnt/β-catenin pathway. Previous studies of our team found that NNK from cigarette significantly induced the acinar cells to experience ADM and PanIN, and accompanied with the activation of LncRNA LINC00857-Wnt/β-catenin pathway. Therefore, we speculate that NNK could induce the “reprogramming” of acinar cells and initiate the malignant transformation of ADM–PanIN–PDAC. The NNK could influence cell fate through activating LncRNA LINC00857-Wnt/β-catenin pathway and cause PDAC eventually. Our studies will be performed in three levels of clinical pathology, cell biology and transgenic animals. To prove the hypothesis, a variety of technology would be applied, including laser confocal microscopy, molecular biology technology, 3D cell culture model, cell lineage tracing, mass spectrometric analysis; small animal imaging technology and so on. This important research will help us to explore the carcinogenic effect of cigarette on the malignant transformation from ADM to PDAC, clarify the molecular mechanisms of it and provide new insights and theory for prevention and treatment of PDAC.