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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metabolism

Background:

• Sustained thymidylate synthase (TYMS) overexpression is a biomarker for drug resistance and poor prognosis in advanced solid tumors, including pancreatic neuroendocrine tumors (PanNETs).
• TYMS is crucial for DNA synthesis, but its overexpression suggests roles beyond nucleotide metabolism.

Purpose of the Study:

• To investigate the role of TYMS in regulating cancer metabolism and signaling pathways in PanNETs.
• To explore the link between TYMS, the AMPK-mTOR axis, and therapeutic response in PanNETs.

Main Methods:

• Proteomic analysis to identify TYMS-regulated proteins involved in metabolism.
• Investigating the impact of TYMS inhibition and overexpression on the AMPK-mTOR signaling pathway in PanNET cells and a transgenic mouse model.
• Correlating TYMS expression with mTOR-associated genes in patient-derived PanNET samples.

Main Results:

• TYMS regulates proteins involved in energy-dependent metabolism.
• TYMS directly impacts the AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) signaling pathway.
• TYMS inhibition activates AMPK signaling, while TYMS overexpression suppresses AMPK and enhances mTOR signaling in PanNETs.
• TYMS expression positively correlates with mTOR-associated genes and impacts everolimus efficacy in PanNET patients.

Conclusions:

• TYMS plays a novel role in linking nucleotide metabolism to cancer growth signaling through the regulation of the AMPK-mTOR axis.
• TYMS levels are clinically significant, affecting prognosis and response to mTOR inhibitors like everolimus in PanNET patients.