我们既往研究发现胰腺癌的远处转移依赖于TrkB所介导的癌细胞大聚集体的形成，聚集体中的肿瘤细胞可以通过自体吞噬(Autophagy)对抗来自环境的选择性压力以及失巢凋亡(Anoikis)的发生。更为有趣的是，处于核心的肿瘤细胞似具有干细胞样特征，我们发现这种特征可能与高表达TrkB的肿瘤细胞与骨髓迁徙来的干细胞或本身组织存在的干细胞诱导融合有关。并且聚集体周围的肿瘤细胞似通过相互协作成为保护核心干细胞样瘤细胞转移到靶器官的特洛伊木马（Trojan horse）（如可能通过互噬Interophagy增强聚集体完整性，释放表达TrkB的微囊泡Microvesicles干扰免疫等）。本研究将在我们既往研究基础上进一步验证TrkB介导的细胞融合是胰腺癌转移聚集体中肿瘤细胞获得干细胞特性的途径，对TrkB信号途径的抑制可能通过干扰细胞融合，破坏大聚集体结构以及微囊泡的释放而达到抑制肿瘤转移的发生。

Our previous study revealed that distant metastasis of pancreatic cancer cells rely on TrkB mediated formation of large aggregates. Aggregation of tumor cells in the body by autophagy against the selective pressure from the environment and anoikis occurred. what is more interesting is at the core of the large tumor cell aggregates may have a stem cell-like characteristics. We found that such features may be derived from the fusion of the cancer cells that with high expression of TrkB migrating to bone marrow stem cell or tissue existence itself. peripheral localization of the tumor cells seems to cooperate with each other to protect the core stem cell-like tumor cells transferring to the target organ acting as the Trojan horse (For example, enhancing the integrity of the aggregates by Interophagy, releasing microvesicles that expressing high TrkB to interfere immunity). This study will verify that the cell fusion mediated by TrkB is the key factor for the large aggregates acquiring the characteristics of stem cell. The inhibition of TrkB signaling pathways may interfere cell fusion, destructing the structure of the large aggregates and the microvesicles for inhibiting cancer metastasis.

利用高表达TrkB的胰腺癌细胞株T3M4在失巢状态下诱导转移大聚集体的形成，我们观察到大聚集体细胞可以通过自体吞噬现象供给自我能量达到对抗转移过程中各种选择性压力的作用。并观察到转移聚集体外周肿瘤细胞之间的互噬融合现象。siRNA抑制TrkB的胰腺癌细胞株T3M4在失巢状态下无法形成肿瘤细胞聚集体。我们观察到，高表达TrkB的胰腺癌微囊泡向肝血窦内皮细胞处浸润，而该处恰是肝脏组织本身增值分裂最活跃的干细胞区域。进一步的研究发现，胰腺癌联合肝转移癌存在大量的新生血管现象，这与胰腺癌患者易发生肝脏转移，预后较差可能密切相关，并可能成为潜在的治疗靶点。肝窦内皮细胞分泌血管紧张素II，血管内皮生长因子及血小板衍生生长因子，导致肝窦毛细血管化及诱发血管拟态的芽生。而进一步的临床转化研究中发现，循环TrkB微囊泡检测评价患者术后及化疗后的转移风险，其与胰腺癌患者的DFS，PFS显著相关，后期临床Nomogram预测模型，以及DCA曲线正在随访构建中。