Role of NEK2 in tumorigenesis and tumor progression.

Never in mitosis A (NIMA)-related kinase 2 (NEK2) is a serine/threonine kinase found in the nucleus and cytoplasm throughout the cell cycle. NEK2 is overexpressed in many cancers and is a biomarker of poor prognosis. Factors contributing to NEK2 elevation in cancer cells include oncogenic transcription factors, decreased ubiquitination, DNA methylation, and the circular RNA (circRNA)/long noncoding RNA (lncRNA)-miRNA axis. NEK2 overexpression produces chromosomal instability and aneuploidy, thereby enhancing cancer progression and suppressing antitumor immunity, which highlights the prominence of NEK2 in tumorigenesis and tumor progression. Small-molecule inhibitors targeting NEK2 have demonstrated promising therapeutic potential in vitro and in vivo across various cancer types. This review outlines the regulatory mechanisms of NEK2 expression, emphasizes its functional roles in cancer initiation and progression, and highlights the anticancer properties of NEK2 inhibitors.

Proteogenomic analysis of melanoma brain metastases from distinct anatomical sites identifies pathways of metastatic progression.

Melanoma brain metastases (MBM) portend a grim prognosis and can occur in up to 40% of melanoma patients. Genomic characterization of brain metastases has been previously carried out to identify potential mutational drivers. However, to date a comprehensive multi-omics approach has yet to be used to analyze brain metastases. In this case report, we present an unbiased proteogenomics analyses of a patient's primary skin cancer and three brain metastases from distinct anatomic locations. We performed molecular profiling comprised of a targeted DNA panel and full transcriptome as well as proteomics using mass spectrometry. Phylogeny demonstrated that all MBMs shared a SMARCA4 mutation and deletion of 12q. Proteogenomics identified multiple pathways upregulated in the MBMs compared to the primary tumor. The protein, PIK3CG, was present in many of these pathways and had increased gene expression in metastatic melanoma tissue from the cancer genome atlas data. Proteomics demonstrated PIK3CG levels were significantly increased in all 3 MBMs and this finding was further validated by immunohistochemistry. In summary, this case report highlights the potential role of proteogenomics in identifying pathways involved in metastatic tumor progression. Furthermore, our multi-omics approach can be considered to aid in precision oncology efforts and provide avenues for therapeutic innovation.

Hypoxia-derived exosomes induce putative altered pathways in biosynthesis and ion regulatory channels in glioblastoma cells.

Hypoxia, a hallmark characteristic of glioblastoma (GBM) induces changes in the transcriptome and the proteome of tumor cells. We discovered that hypoxic stress produces significant qualitative and quantitative changes in the protein content of secreted exosomes from GBM cells. Among the proteins found to be selectively elevated in hypoxic exosomes were protein-lysine 6-oxidase (LOX), thrombospondin-1 (TSP1), vascular derived endothelial factor (VEGF) and a disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1), well studied contributors to tumor progression, metastasis and angiogenesis. Our findings demonstrate that hypoxic exosomes induce differential gene expression in recipient glioma cells. Glioma cells stimulated with hypoxic exosomes showed a marked upregulation of small nucleolar RNA, C/D box 116-21 (SNORD116-21) transcript among others while significantly downregulated the potassium voltage-gated channel subfamily J member 3 (KCNJ3) message. This differential expression of certain genes is governed by the protein cargo being transferred via exosomes. Additionally, compared to normoxic exosomes, hypoxic exosomes increased various angiogenic related parameters vis-à-vis, overall tube length, branching intervals and length of isolated branches studied in tube formation assay with endothelial progenitor cells (EPCs). Thus, the intercellular communication facilitated via exosomes secreted from hypoxic GBM cells induce marked changes in the expression of genes in neighboring normoxic tumor cells and possibly in surrounding stromal cells, many of which are involved in cancer progression and treatment resistance mechanisms.