4.7 Article

Neural signaling modulates metabolism of gastric cancer

期刊

ISCIENCE
卷 24, 期 2, 页码 -

出版社

CELL PRESS
DOI: 10.1016/j.isci.2021.102091

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资金

  1. Liaison Committee [46056636/46056928/90061700/90061701]
  2. Joint Program of the Medical Faculty of NTNU
  3. St. Olavs University Hospital
  4. Cancer Foundation of St. Olavs Hospital (Kreftfondet ved St. Olavs hospital)
  5. Faculty of Medicine and Health Sciences at NTNU
  6. RHF

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The study identified a link between neural signaling and tumor metabolism, proposing a therapeutic strategy targeting nerve-cancer metabolism which demonstrated efficacy in mouse models and feasibility in patients.
Tumors comprise cancer cells and the associated stromal and immune/inflammatory cells, i.e., tumor microenvironment (TME). Here, we identify a metabolic signature of human and mouse model of gastric cancer and show that vagotomy in the mouse model reverses the metabolic reprogramming, reflected by metabolic switch from glutaminolysis to OXPHOS/glycolysis and normalization of the energy metabolism in cancer cells and TME. We next identify and validate SNAP25, mTOR, PDP1/a-KGDH, and glutaminolysis as drug targets and accordingly propose a therapeutic strategy to target the nerve-cancer metabolism. We demonstrate the efficacy of nerve-cancer metabolism therapy by intratumoral injection of BoNT-A (SNAP25 inhibitor) with systemic administration of RAD001 and CPI- 613 but not cytotoxic drugs on overall survival in mice and show the feasibility in patients. These findings point to the importance of neural signaling in modulating the tumor metabolism and provide a rational basis for clinical translation of the potential strategy for gastric cancer.

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