Clinical studies of cancer patients have shown that overexpression or amplification of thymidylate synthase (TS) correlates with a worse clinical outcome. We previously showed that elevated TS exhibits properties of an oncogene and promotes pancreatic neuroendocrine tumors (PanNETs) with a long latency. To study the causal impact of elevated TS levels in PanNETs, we generated a mouse model with elevated human TS (hTS) and conditional inactivation of Men1 gene in pancreatic islet cells (hTS/Men1-/-). We demonstrated that increased hTS expression was associated with earlier tumor onset and accelerated PanNET development as compared to control Men1-/- and Men1+/ΔN3-8 mice. We also observed decrease in overall survival of hTS/Men1+/- and hTS/Men1-/- mice as compared to control mice. We showed that elevated hTS in Men1-deleted tumor cells enhanced cell proliferation, deregulated cell cycle kinetics and was associated with a higher frequency of somatic mutations, DNA damage and genomic instability. In addition, we analyzed survival of 88 PanNET patients and observed that high TS protein expression independently predicted worse clinical outcome. In summary, elevated hTS directly participates in promoting PanNET tumorigenesis with reduced survival in Men1 mutant background. This work will re-focus attention on new strategies to inhibit TS activity for PanNET treatment.
Vinod Vijayakurup, Kyungah Maeng, Hye Seung Lee, Benjamin S. Meyer, Sandra Burkett, Akbar Nawab, Michael W. Dougherty, Christian Jobin, Iqbal Mahmud, Timothy J. Garrett, Michael Feely, Kyoung Bun Lee, Frederic J. Kaye, Maria V. Guijarro, Maria Zajac-Kaye