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

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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.