Integrated proteomic analysis identifies TYMS-dependent AMPK-mTOR signaling in pancreatic neuroendocrine tumors

Vinod Vijayakurup; Benjamin Meyer; Syeda Rida Rizvi; Kara H Kievit; Iram Hyder; Jin Koh; Michael Feely; Maria V Guijarro; Frederic J Kaye; Maria Zajac-Kaye

doi:10.1016/j.isci.2025.113833

Integrated proteomic analysis identifies TYMS-dependent AMPK-mTOR signaling in pancreatic neuroendocrine tumors

iScience. 2025 Oct 24;28(11):113833. doi: 10.1016/j.isci.2025.113833. eCollection 2025 Nov 21.

Authors

Affiliations

¹ Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL 32610, USA.
² ICBR, University of Florida, Gainesville, FL 32610, USA.
³ Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA.
⁴ Department of Medicine, University of Florida, Gainesville, FL 32610, USA.

Abstract

While regulated TYMS expression is essential for DNA synthesis, sustained TYMS overexpression is a key biomarker for drug resistance and poor prognosis in patients with advanced solid tumors, including pancreatic neuroendocrine tumors (PanNETs). Using proteomic analysis, we observed that TYMS regulates proteins involved in energy-dependent metabolism. Further, we demonstrate that TYMS directly impacts the AMPK-mTOR signaling pathway, a critical axis governing the metabolic adaptation of cancer. TYMS inhibition activates AMPK signaling in PanNET cells, while TYMS overexpression suppresses AMPK activation and enhances mTOR signaling in PanNETs arising in TYMS-overexpressing Men1 ^-/- null transgenic mouse model. In addition, TYMS expression positively correlates with mTOR-associated genes in patients with PanNET. TYMS levels also impact the efficacy of everolimus, an FDA-approved mTOR inhibitor for patients with PanNET, underscoring the clinical significance of our findings. In summary, our study uncovers a new role of TYMS linking nucleotide metabolism to growth signaling pathways via the regulation of the AMPK-mTOR axis.

Keywords: Cancer; Molecular biology; Proteomics.