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Tumor associated macrophages potentiate CDON marks cells composed invasive margin advancing in liver metastasis of gastric cancer

ABSTRACT: 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.

ORGANISM(S): Mus Musculus

SUBMITTER: Chunchao Zhu

PROVIDER: PXD066584 | iProX | Fri Jul 25 00:00:00 BST 2025

REPOSITORIES: iProX

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Project description:Spontaneous metastasis of gastric carcinoma to secondary organs is seldom reproduced in the mice. In this study, we established highly reproducible, experimental mice model in which gastric carcinoma progressively grows in the site of gastric walls and metastasize to secondary sites. A highly tumorigenic GC cells were engineered to express type 2 luciferase and injected via orthotopic route into BALB/c nude mice. The mice developed highly progressive GC tumors in the gastric wall where implanted and slow metastases to liver, spleen, lung, kidney and ovary, with rate of metastases to ovary being 63.6% of implanted mice. The tumors colonized in the ovary expressed a GI marker MUC5A, suggestive of typical human Krukenberg tumor. Immuno-histochemical stainings revealed that many mesenchymal markers were strongly positive in motile tumor cells in the vein of ovary and became gradually weak during extravasations to colonize in the ovary. When routes of metastasis were further investigated, the mesenchymal marker SMA stained low in the tumor cells of the primary site of stomach wall, became high in intravasating vein in the stomach wall, remained high in extravasating veins in the liver and ovary and finally returned low in the colonized tumor in the liver and ovary. However, expression of an epithelial marker Claudin did not show in the opposite profile to SMA, indicating that acquisition of mesenchymal phenotypes rather than loss of epithelial characteristics may more give rise to metastatic potential. Dissociated cells derived from tumors in the implanted mouse stomach or metastasized to ovaries retain their tumorigenicity and metastatic potentials. The mRNA microarray and Western blot analyses showed that metastatic tumor-derived cells showed significantly higher expression of GAGE12 gene family than orthotopic tumors-derived cells. The shRNA-mediated knock-down of the GAGE12 family in the metastatic tumors-derived cells abolished the tumor formation in gastric wall and metastasis as well. In conclusion, we established an in vivo orthotopic gastric cancer mouse model spontaneously metastasizing to secondary organs including ovary, which exhibits typical characteristics of a Krukenberg tumor. Expression of mesenchymal markers should be functionally associated with the gain of metastatic ability in this study. A hightly tumorigenic gastric carcinoma SNU-16 cells were orthotpically injected into stomach wall. Tumors formed in the stomach wall (16S) and mestasized to ovary (16O) were dissociated and cultured for 7 day. These cells were re-injected orthotopically and tumors formed in the stomach from 16S (16SS) and ovary from 16O injection (16OO) were dissociated. Total RNAs were isolated from 16S, 16SS, 16O and 16OO2 and subjected to mRNA microarrays

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Tumor associated macrophages potentiate CDON marks cells composed invasive margin advancing in liver metastasis of gastric cancer

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