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

doi:10.1016/j.isci.2021.102091

Neural signaling modulates metabolism of gastric cancer

iScience. 2021 Jan 22;24(2):102091. doi: 10.1016/j.isci.2021.102091. eCollection 2021 Feb 19.

Authors

Hanne-Line Rabben^{1

2}, Gøran Troseth Andersen¹, Magnus Kringstad Olsen¹, Anders Øverby¹, Aleksandr Ianevski¹, Denis Kainov¹, Timothy Cragin Wang^{1

3}, Steinar Lundgren^{1

4}, Jon Erik Grønbech^{1

5}, Duan Chen¹, Chun-Mei Zhao^{1

2}

Affiliations

¹ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway.
² The Central Norway Regional Health Authority, Norway.
³ Division of Digestive and Liver Diseases, Columbia University College of Physicians and Surgeons, New York, NY 10032-3802, USA.
⁴ Cancer Clinic, St. Olavs Hospital, Trondheim University Hospital, 7006 Trondheim, Norway.
⁵ Surgical Clinic, St. Olavs Hospital, Trondheim University Hospital, 7006 Trondheim, Norway.

Abstract

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.

Keywords: Cancer; Cancer Systems Biology.