胰腺局部炎症通过TGFβR及EGFR信号通路增强胰腺癌侵袭力的机制研究

Clinical studies and meta-analysis suggested that concurrent chemoradiotherapy failed to significantly improve the prognosis of patients with pancreatic cancer, even though some of them showed some benefit. One reason might be chemoradiotherapy increased the risk of distant metastasis. As a major component of the pancreas, pancreatic acinar cells did not receive enough attention of its effect on the invasiveness of pancreatic cancer. However, the acinar cells around the tumor would undergo necrosis and induce local inflammation during concurrent chemoradiotherapy as planned target volume (PTV) generally included some normal tissues around the tumor and chemotherapeutic drugs would damage normal cells. This project, based on our previous research outcomes, pre-experiment results and literature reading, hypothesized that recruited M2 macrophages during this local pancreatic inflammation might activate TGFβR and EGFR signaling pathways, the EGFR signaling pathway would promote the degradation of SMAD4 and attenuate its role on inhibiting phosphorylation of IκBα and activation of NF-κB induced by TGFβ1, the activated NF-κB would then translocate into the nucleus, promoting epithelial-mesenchymal transition (EMT) and distant metastasis of pancreatic cancer. The project will help us further understand the mechanism of concurrent chemoradiotherapy in promoting distant metastasis among some patients, and might provide solutions to improve their prognosis.

临床研究及meta分析显示，尽管部分胰腺癌患者能从同步放化疗中获益，同步放化疗并未从整体上改善胰腺癌患者的预后，原因之一可能是其增加了部分患者发生远处转移的风险。作为胰腺主要组成成分，胰腺腺泡细胞是否影响胰腺癌的侵袭力少有研究。但同步放化疗时，由于计划靶区常包括肿瘤周边部分正常组织，且化疗药物也会损伤正常细胞，故肿瘤周边的胰腺腺泡细胞可能发生坏死，诱发局部炎症反应。本课题基于前期研究工作基础，预实验及文献阅读，提出该炎症反应伴随的M2型巨噬细胞浸润可能激活胰腺癌细胞的TGFβR及EGFR信号通路，其中EGFR信号通路促进SMAD4降解，使TGFβ1磷酸化IκBα并激活NF-κB这一生物学效应受SMAD4的抑制减弱，而被激活的NF-κB转运进细胞核，促进胰腺癌细胞发生EMT及远处转移。本课题的开展，将有助于我们了解部分患者接受同步放化疗时容易发生远处转移的机制，并为改善其预后提供思路。

血管新生的异常调解在肿瘤的发生发展中发挥重要作用，一些抗血管生成靶向药如贝伐珠单抗、安罗替尼已成为多个肿瘤的主要治疗方案之一。但多个III期临床研究发现抗血管生成靶向药并未改善胰腺癌患者的预后，其背后的原因并未得到阐明。本课题首先通过CCK-8、划痕实验及侵袭实验，发现安罗替尼对胰腺癌细胞株有显著的杀伤作用。转录组学以及IPA生物通路分析结果发现安罗替尼主要调控DNA损伤及细胞周期相关通路，蛋白组学及磷酸化组学联合分析发现，安罗替尼主要调控核糖体及RNA转运等相关蛋白的表达水平及磷酸化水平。基于安罗替尼多组学结果，我们通过LASSO回归分析方法，筛选出5个关键基因，构建了安罗替尼相关的危险指数，通过多个胰腺癌相关的公共数据集分析，该危险指数能够将胰腺癌患者区分成两种类型，其中高危患者预后差，可能对安罗替尼治疗敏感。本研究通过多组学研究，初步揭示了安罗替尼杀伤胰腺癌的分子机制，为开展安罗替尼治疗胰腺癌的临床研究提供了依据，并且根据组学构建的危险指数有助于筛选可能对安罗替尼敏感的患者，为临床精准治疗提供依据。