Lysyl Oxidase Enhances Warburg Effect to Mediate Reciprocal Interactions between Tumor Cells and Cancer Associated Fibroblasts in Liver Metastasis of Gastric Cancer

Background: Liver is one of the most preferred destinations of distant metastasis in gastric cancer (GC). As effective treatment is still limited, the prognosis of GC patients bearing liver metastasis is poor. We filter out lysyl oxidase (LOX) to study its function in the tumor microenvironment (TME) and seek for potential therapeutic targets. Methods: Transcription analysis on 6 cases of liver metastasis of GC patients with respective paired primary tumors and adjacent normal livers was performed. The filtration out of LOX was done using 5 datasets. 69 GC liver metastasis tissues were utilized to perform immunohistochemistry (IHC) and analyze prognosis. Computed Tomography (CT) combined 3D organ reconstruction bioluminescence imaging was performed to precisely evaluate the metastatic tumor burden on liver of intrasplenic injection mouse model. Human and mouse cancer associated fibroblasts (CAFs) in liver metastasis were separated to culture to study the interaction of LOX and TGF-β1. Patients-derived xenograft (PDX) model was established using liver metastasis of patients to evaluate the therapeutic value of LOX inhibitor β‐aminopropionitrile (BAPN). Results: CAFs-derived LOX at liver metastatic niche of GC promotes niche formation and outgrowth thus predicts poor prognosis. Meanwhile tumor cells in niche secrete TGF-β1 to nourish CAFs and stimulate them to produce more LOX in turn. The mechanism involved in LOX-mediated proliferation facilitation is enhancement of Warburg effect. The inhibitor of LOX, BPAN could hamper the effect brought by LOX in vivo and in vitro. Interpretation: Our study has unveiled a positive feedback loop between CAFs and tumor cells in liver metastasis niche of GC. The core molecule is LOX which facilitates Warburg effect. Targeting LOX with its inhibitor BAPN might serve as a potential therapeutic strategy. Funding Statement: This research is supported by the national natural science foundation of China (31872740), The 100-member plan of the Shanghai municipal commission of health and family planning (2017BR043), Shanghai science and technology commission project (17ZR1416800), Renji hospital training fund (PYMDT-003, PYIII-17-015). National Natural Science Foundation of China (81672358, to Z.-G. Zhang), the Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support (20181708, to Z.-G. Zhang), Program of Shanghai Academic/Technology Research Leader (19XD1403400, to Z.-G. Zhang), Science and Technology Commission of Shanghai Municipality (18410721000, to Z.-G. Zhang) and Shanghai Municipal Health Bureau (2018BR32, to Z.-G. Zhang). National Natural Science Foundation of China, No. 81701945. Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: The whole process of specimen collection and experiment performance were approved by the local ethics committee in Renji Hospital, with all patients’ informed consents.