Zhejiang University: Scientists uncover a new tumor cells-fibroblasts juxtacrine signaling that promotes gastric cancer metastasis

The interaction between tumor cells and cells in the microenvironment is crucial for tumor metastasis. At present, there is an in-depth understanding of paracrine signaling-mediated cell-to-cell interactions in the tumor microenvironment and its role in tumor metastasis. For example, during the progression of gastric cancer, a variety of cytokines, growth factors and extracellular matrix proteins have been reported to promote the progression and metastasis of tumor cells. Clinically, we have noticed a phenomenon for a long time. Whether it is a solid primary tumor or a metastatic tumor tissue, many tumor cells closely contact with stromal cells, especially those tumor cells at the frontier of invasion. The direct cell-cell contact is usually mediated by juxtacrine signaling. However, the roles of juxtacrine signaling in gastric cancer metastasis remains unclear.

Recently, the research group led by Prof. ZHUO Wei and Prof. ZHOU Tianhua at the School of Basic Medicine of Zhejiang University published a research paper entitled Cadherin 11-mediated juxtacrine interaction of gastric cancer cells and fibroblasts promotes metastasis via YAP/tenascin-C signaling in Science Bulletin. They uncovered a novel mechanism by which Cadherin 11-mediated juxtacrine signaling in gastric cancer cells and fibroblasts activates the YAP/Tenascin-C axis to promote gastric cancer metastasis.

The Cadherins family is a class of transmembrane glycoproteins that mediate the juxtacrine signaling between cells. The researchers took cadherins as the entry point to study the role of juxtacrine in gastric cancer. They used the Cancer Genome Atlas (TCGA) database and multiple gastric cancer sample validation cohorts to systematically screen the cadherins family. It was found that cadherin 11 (CDH11) was the only adhesion molecule member whose expression was significantly up-regulated in gastric cancer tissue, correlated with TNM stage, and significantly with poor prognosis of patients. Mouse experiments suggest that CDH11 plays a key role in gastric cancer cell metastasis. Next, the researchers analyzed the relationship between CDH11 and various microenvironmental cells, and found that the expression level of CDH11 in gastric cancer tissue was closely related to the markers of cancer associated fibroblasts (CAFs), suggesting that CDH11 may be involved in the interaction between gastric cancer cells and CAFs. Moreover, the researchers established in vitro cell-cell adhesion models, co-culture models, and in vivo co-metastasis models. They found that CDH11 mediates the adhesion interaction between gastric cancer cells and fibroblasts, and promotes the migration of gastric cancer cells, tumor sphere formation, and in vivo metastasis. Mechanistically, the researchers revealed that CDH11-mediated juxtacrine between gastric cancer cells and fibroblasts can activate the YAP signaling pathway in gastric cancer cells, promote the localization of YAP in the nucleus, and upregulate the transcriptional expression of Tenascin-C (TNC). Further rescue assays verified that the YAP pathway and target gene TNC are involved in the promotion of gastric cancer cell migration, tumor sphere formation induced by CDH11. Finally, data from multiple gastric cancer sample cohorts indicated that CDH11, YAP, and TNC were up-regulated in gastric cancer, and the expression levels of these genes were closely correlated and significantly correlated with poor prognosis in gastric cancer patients.

In conclusion, this study elucidates the important role of juxtacrine in the interaction between gastric cancer cells and tumor associated fibroblasts and in gastric cancer metastasis. The CDH11-YAP-TNC juxtacrine signaling revealed by this work will be helpful in understanding cell communications in tumor microenvironment. Furthermore, this work also provides potential targets for the clinical treatment and prognosis of gastric cancer metastasis.

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