Anti-EREG monoclonal antibody, clone 290722

Glioma is the most common primary brain tumor in humans and the most deadly. Stem cells, which are characterized by therapeutic resistance and self-renewal, play a critical role in glioma, and therefore the identification of stem cell-related genes in glioma is important. In this study, we collected and evaluated the epigenetically regulated-mRNA expression-based stemness index (EREG-mRNAsi) of The Cancer Genome Atlas (TCGA, ) for glioma patient samples, corrected through tumor purity. After EREG-mRNAsi correction, glioma pathological grade and survival were analyzed. The differentially expressed gene (DEG) co-expression network was constructed by weighted gene co-expression network analysis (WGCNA) in TCGA glioma samples to find modules of interest and key genes. Gene ontology (GO) and pathway-enrichment analysis were performed to identify the function of significant genetic modules. Protein-protein interaction (PPI) and co-expression network analysis of key genes was performed for further analysis. In this experiment, we found that corrected EREG-mRNAsi was significantly up-regulated in glioma samples and increased with glioma grade, with G4 having the highest stemness index. Patients with higher corrected EREG-mRNAsi scores had worse overall survival. Fifty-one DEGs in the brown gene module were found to be positively related to EREG-mRNAsi via WGCNA. GO and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that chromosome segregation and cell cycle molecular function were the major functions in key DEGs. Among these key DEGs, BUB1 showed high connectivity and co-expression, and also high connectivity in PPI. Fifty-one key genes were verified to play a critical role in glioma stem cells. These genes may serve as primary therapeutic targets to inhibit the activity of glioma stem cells.

Recent genomic studies challenge the conventional model that each metastasis must arise from a single tumor cell and instead reveal that metastases can be composed of multiple genetically distinct clones. These intriguing observations raise the question: How do polyclonal metastases emerge from the primary tumor? In this study, we used multicolor lineage tracing to demonstrate that polyclonal seeding by cell clusters is a frequent mechanism in a common mouse model of breast cancer, accounting for >90% of metastases. We directly observed multicolored tumor cell clusters across major stages of metastasis, including collective invasion, local dissemination, intravascular emboli, circulating tumor cell clusters, and micrometastases. Experimentally aggregating tumor cells into clusters induced a >15-fold increase in colony formation ex vivo and a >100-fold increase in metastasis formation in vivo. Intriguingly, locally disseminated clusters, circulating tumor cell clusters, and lung micrometastases frequently expressed the epithelial cytoskeletal protein, keratin 14 (K14). RNA-seq analysis revealed that K14(+) cells were enriched for desmosome and hemidesmosome adhesion complex genes, and were depleted for MHC class II genes. Depletion of K14 expression abrogated distant metastases and disrupted expression of multiple metastasis effectors, including Tenascin C (Tnc), Jagged1 (Jag1), and Epiregulin (Ereg). Taken together, our findings reveal K14 as a key regulator of metastasis and establish the concept that K14(+) epithelial tumor cell clusters disseminate collectively to colonize distant organs.