Elucidating the role of cancer stem cells in the metastatic progression of pancreatic neuroendocrine tumors

胰腺神经内分泌肿瘤(PanNETs)是一种高度异质性的肿瘤，因此开发一种有效的治疗方法是具有挑战性的。基因组分析显示，这些肿瘤通常不存在典型的癌症相关基因突变，如p53。尽管它们在独特的与Pannet相关的基因中存在突变，如man-1。然而，关于肿瘤发生的机制，特别是这些肿瘤的异质性，仍然缺乏许多知识。在这个项目中，我使用多模式方法分析了肿瘤间和肿瘤内的异质性，并确定了Pannet肿瘤发生的一些关键节点。具体地说，我已经证明了当MEN-1突变发生时，Notch通路和P53在Pannet中交织在一起，促进肿瘤的发生。最有趣的是，我已经确定胰岛素瘤相关-1(INSM1)是当MEN1丢失和P53为野生型时早期PANet细胞增殖的关键标志。这些数据表明PanNETs中特定的基因组变化影响它们的肿瘤发生。考虑到目前缺乏根据基因组异常对所有Pannet患者进行分层的系统，这些发现可能因此为改善未来的临床决策和改善Pannet患者的预后提供机会。

Pancreatic neuroendocrine tumors (PanNETs) are highly heterogeneous tumors and for this reason developing a curative treatment has been proven challenging. Genomic analysis revealed that these tumors often do not harbor mutations in typical cancer-related genes such as p53. Although they harbor mutation in unique PanNET-related genes such as MEN-1. Still, much knowledge is missing on the mechanisms of tumorigenesis and specifically on the heterogeneity of these tumors. Using a multimodal approach in this project I have analysed both the inter- and intra- tumor heterogeneity and I have identified some of the crucial nodes of PanNET tumorogenesis. Specifically, I have demonstrated that the Notch pathway and p53 intertwine in PanNET to promote tumorigenesis when MEN-1 mutations occur. Most interestingly, I have identified insulinoma associated-1 (INSM1) as a key marker of proliferation in PanNET early onset when MEN1 is lost and p53 is wildtype.These data suggest that specific genomic alterations in PanNETs influence their tumorigenesis. Considering the current lack of a system to stratify all PanNET patients based on their genomic abnormalities, these findings may thereby provide an opportunity to improve future clinical decisions and improve the prognosis of PanNET patients.