RYK, a receptor of noncanonical Wnt ligand Wnt5a, is positively correlated with gastric cancer tumorigenesis and potential of liver metastasis.

Gastric cancer (GC) is the most prevalent human cancer around the globe. In GC, Wnt signaling is deregulated, and receptor-like tyrosine kinase (RYK) coreceptors have been identified to interact with noncanonical Wnt ligand Wnt5a. We, therefore, aimed to evaluate the role of RYK in GC development and metastasis. GC tumor samples were collected from 250 GC patients. Expressions of RYK, as well as markers for the epithelial-mesenchymal transition (EMT), such as N-cadherin and E-cadherin, were subjected to correlation analysis with clinicopathological features. Endogenous RYK expression levels were compared in GC cell lines with ascending metastatic potentials followed by stable RYK knockdown. Effect of RYK knockdown on GC cell migration, invasion, and EMT phenotype were assessed in vitro, and on GC tumor growth in vivo in a xenograft rodent model. Particularly, liver metastasis potential of tail vein-injected GC cells was also analyzed following RYK knockdown. RYK was highly correlated with liver metastasis of GC tumors and the expression profiles of EMT markers toward the mesenchymal tendency. RYK expression was also positively correlated with the metastasis potential of GC cells. RYK knockdown not only inhibited migration, invasion, and EMT of GC cells in vitro, but also suppressed tumorigenesis and liver metastasis of GC cells in vivo using the mouse xenograft model. RYK is highly correlated with GC tumorigenesis and potential of liver metastasis, suggesting it may be a novel oncogenic factor of the noncanonical Wnt signaling pathway contributing to GC.NEW & NOTEWORTHY RYK is highly correlated with gastric cancer tumorigenesis and the potential of liver metastasis, suggesting it may be a novel oncogenic factor of the noncanonical Wnt signaling pathway contributing to gastric cancer.

(-)-4-O-(4-O-ß-D-glucopyranosylcaffeoyl) Quinic Acid Inhibits the Function of Myeloid-Derived Suppressor Cells to Enhance the Efficacy of Anti-PD1 against Colon Cancer.

PURPOSE: Immunotherapy in the clinic has demonstrated its potential to control cancer through disinhibiting the immune system, especially for immune checkpoint inhibitors such as anti-programmed cell death protein 1/anti-programmed death-ligand 1 (anti-PD1/anti-PD-L1). However, although these new immunotherapies have resulted in durable clinical responses in various cancers, multiple mechanisms of immune resistance and suppression exist in tumors. One significant barrier to efficacy of anti-PD1 against colon cancer may be the recruitment of myeloid-derived suppressor cells (MDSCs) into the tumor microenvironment. Here we demonstrated functional inhibition of G-MDSC with (-)-4-O-(4-O-ß-D-glucopyranosylcaffeoyl) quinic acid (QA), an inhibitor of PI3Kδ/γ, reshaped the tumor immune microenvironment and promoted cytotoxic T cell-mediated tumor regression, resultantly enhancing responses to anti-PD1 treatment in colon tumor model. METHODS: A syngeneic colon tumor mouse model was used to study the effects of QA on tumor immune microenvironment and its potential synergistic effects with anti-PD1 blockade. RESULTS: QA treatment inhibited G-MDSC function in the tumor tissue. Additionally, combination treatment induced CD8+ T lymphocyte-dependent tumor growth delay and prolonged survival time in colon cancer. CONCLUSIONS: Our results offered opportunities for new combination strategies using a selective small molecule PI3Kδ/γ inhibitor, to suppress MDSCs to enhance responses to immune checkpoint blockade in colon cancer.