Neural signaling modulates metabolism of gastric cancer
Hanne-Line Rabben,
Gøran Troseth Andersen,
Magnus Kringstad Olsen,
Anders Øverby,
Aleksandr Ianevski,
Denis Kainov,
Timothy Cragin Wang,
Steinar Lundgren,
Jon Erik Grønbech,
Duan Chen,
Chun-Mei Zhao
Affiliations
Hanne-Line Rabben
Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway; The Central Norway Regional Health Authority, Norway
Gøran Troseth Andersen
Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway
Magnus Kringstad Olsen
Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway
Anders Øverby
Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway
Aleksandr Ianevski
Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway
Denis Kainov
Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway
Timothy Cragin Wang
Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway; Division of Digestive and Liver Diseases, Columbia University College of Physicians and Surgeons, New York, NY 10032-3802, USA
Steinar Lundgren
Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway; Cancer Clinic, St. Olavs Hospital, Trondheim University Hospital, 7006 Trondheim, Norway
Jon Erik Grønbech
Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway; Surgical Clinic, St. Olavs Hospital, Trondheim University Hospital, 7006 Trondheim, Norway
Duan Chen
Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway
Chun-Mei Zhao
Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway; The Central Norway Regional Health Authority, Norway; Corresponding author
Summary: 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/α-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.
