Tumor associated macrophages potentiate CDON marks cells composed invasive margin advancing in liver metastasis of gastric cancer
Tumor microenvironment (TME) contributes to liver metastasis of gastric cancer (GC) which leads to poor prognosis. Invasive margin (IM) of metastatic niche provides vital advantage for metastatic niches growth via reconstruction of surrounding TME, during which tumor-associated macrophages (TAMs) plays important roles. Liver samples from 69 GC patients containing inner part liver metastatic niches (inner-LM), adjacent liver (AL) and IM with their matched primary tumors or 632 cases of human tissue samples of primary GC were involved in this study, and we have discovered that IM tumor cell expressed cell adhesion associated, oncogene regulated (CDON) plays important roles in metastasis progression. Spatial analysis on whole scan of IHC-P or immunofluorescence (IF) have demonstrated that the expression pattern of CDON is restricted to tumor cells at IM but not inner-LM area in accordance with the distribution of infiltrated TAMs derived SPARC. Verification of SPARC-CDON axis in liver metastasis was performed on samples mentioned before and the importance of which was further confirmed via Trp53R172H/+/Cdhfl/fl/Atp4b-Cre (TPA) mouse model or intrasplenic injection on clodronate or bone marrow chimeric mouse models assessed by CT combined in vivo imaging with organ reconstruction. The mechanism was studied by co-immunoprecipitation, proximity ligation assay and migration assay through automatic live cell workstation. The therapeutic value of SPARC-CDON axis was evaluated via ex vivo test, the patient derived xenograft (PDX) model and patient derived organoids (PDOs). We have unveiled that SPARC-CDON axis facilitates the growth of GC liver metastasis through promotion of IM formation and expansion via triggering noncanonical hedgehog pathway, indicating the potential therapeutic targets in clinical.