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

阐明癌症干细胞在胰腺神经内分泌肿瘤转移进展中的作用

基本信息

批准号：
21K15498
负责人：
カポダッノイレニア
金额：
$ 2.08万
依托单位：
National Cancer Center Japan
依托单位国家：
日本
项目类别：
Grant-in-Aid for Early-Career Scientists
财政年份：
2021
资助国家：
日本
起止时间：
2021-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-21K15498/
关键词：
notch pathway p53 diagnostic marker MEN1 cancer stem cells PNETs diagnostic markers metastases

项目摘要

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.

胰腺神经内分泌肿瘤（PanNET）是高度异质性的肿瘤，因此开发治愈性治疗已被证明具有挑战性。基因组分析显示，这些肿瘤通常不会在典型的癌症相关基因（如p53）中发生突变。尽管它们在独特的PanNET相关基因（如MEN-1）中存在突变。尽管如此，许多知识是缺乏对肿瘤发生的机制，特别是对这些肿瘤的异质性。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。具体来说，我已经证明了Notch通路和p53介导的PanNET，以促进肿瘤发生时，MEN-1突变发生。最有趣的是，当MEN 1丢失且p53为野生型时，我已经确定胰岛素瘤相关-1（INSM 1）是PanNET早期发病增殖的关键标志物。考虑到目前缺乏一个系统来分层所有PanNET患者的基因组异常的基础上，这些发现可能因此提供了一个机会，以改善未来的临床决策和改善PanNET患者的预后。